In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp

Current Drug Metabolism

Volumn 12, Issue 8, 2011, Pages 750-773

  Mudra, Daniel R ^a   Desino, Kelly E ^a   Desai, Prashant V ^b  

^a ELI LILLY AND COMPANY   (United States)

^b ABBOTT LABORATORIES   (United States)

Author keywords

Cytochrome P450; In silico modeling; In situ models; In vitro models; Metabolic enzymes; P glycoprotein; Transporter enzyme interplay; Transporters

Indexed keywords

ABC TRANSPORTER; BROMOCRIPTINE; CYCLOSPORIN; CYCLOSPORIN A; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C18; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 2J2; CYTOCHROME P450 3A; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; ELACRIDAR; ERYTHROMYCIN; FELODIPINE; FIBRINOGEN RECEPTOR ANTAGONIST; GLYCOPROTEIN P; INDINAVIR; KETOCONAZOLE; ME 3229; METYRAPONE; MIDAZOLAM; MULTIDRUG RESISTANCE PROTEIN 1; RAPAMYCIN; TRAMAZOLINE; UNCLASSIFIED DRUG; VALSPODAR; VERAPAMIL;

BINDING AFFINITY; BINDING SITE; COMPUTER MODEL; CRYSTAL STRUCTURE; CULTURE TECHNIQUE; DIFFUSION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG TRANSPORT; HUMAN; IN VITRO STUDY; MOLECULAR DOCKING; MOLECULAR WEIGHT; NONHUMAN; PROTEIN EXPRESSION; PROTEIN MODIFICATION; PROTEIN STRUCTURE; REVIEW; SANDWICH CULTURED HEPATOCYTE; STRUCTURE ACTIVITY RELATION;

EID: 80053471751     PISSN: 13892002     EISSN: 18755453     Source Type: Journal    
DOI: 10.2174/138920011798356999     Document Type: Review

References (296)

1. Benet, L. Z.; Izumi, T.; Zhang, Y.; Silverman, J. A.; Wacher, V. J.Intestinal MDR transport proteins and P-450 enzymes as barriers tooral drug delivery. J. Control Release, 1999, 62(1-2), 25-31. (Pubitemid 29486478)
2. Doherty, M. M.; Charman, W. N. The mucosa of the smallintestine: how clinically relevant as an organ of drug metabolism?Clin. Pharmacokinet., 2002, 41(4), 235-253. (Pubitemid 34533755)
3. Doherty, M. M.; Pang, K. S. First-pass effect: significance of theintestine for absorption and metabolism. Drug Chem. Toxicol.,1997, 20(4), 329-344. (Pubitemid 28078544)
4. Giacomini, K. M.; Huang, S. M.; Tweedie, D. J.; Benet, L. Z.;Brouwer, K. L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.;Hillgren, K. M.; Hoffmaster, K. A.; Ishikawa, T.; Keppler, D.;Kim, R. B.; Lee, C. A.; Niemi, M.; Polli, J. W.; Sugiyama, Y.;Swaan, P. W.; Ware, J. A.; Wright, S. H.; Yee, S. W.; Zamek-Gliszczynski, M. J.; Zhang, L. Membrane transporters in drugdevelopment. Nat. Rev. Drug Discov., 2010, 9(3), 215-236.
5. Hall, S. D.; Thummel, K. E.; Watkins, P. B.; Lown, K. S.; Benet,L. Z.; Paine, M. F.; Mayo, R. R.; Turgeon, D. K.; Bailey, D. G.;Fontana, R. J.; Wrighton, S. A. Molecular and physicalmechanisms of first-pass extraction. Drug Metab. Dispos., 1999,27(2), 161-166.
6. Ho, R. H.; Kim, R. B. Transporters and drug therapy: implicationsfor drug disposition and disease. Clin. Pharmacol. Ther., 2005,78(3), 260-277. (Pubitemid 41254111)
7. Lin, J. H.; Chiba, M.; Baillie, T. A. Is the role of the small intestinein first-pass metabolism overemphasized? Pharmacol. Rev., 1999,51(2), 135-158.
8. Mouly, S. J.; Paine, M. F.; Watkins, P. B. Contributions ofCYP3A4, P-glycoprotein, and serum protein binding to theintestinal first-pass extraction of saquinavir. J. Pharmacol. Exp.Ther., 2004, 308(3), 941-948. (Pubitemid 38263969)
9. Paine, M. F.; Oberlies, N. H. Clinical relevance of the smallintestine as an organ of drug elimination: drug-fruit juiceinteractions. Expert Opin. Drug Metab. Toxicol., 2007, 3(1), 67-80. (Pubitemid 47307455)
10. Shugarts, S.; Benet, L. Z. The role of transporters in thepharmacokinetics of orally administered drugs. Pharm. Res., 2009,26(9), 2039-2054.
11. Suzuki, H.; Sugiyama, Y. Role of metabolic enzymes and effluxtransporters in the absorption of drugs from the small intestine.Eur. J. Pharm. Sci., 2000, 12(1), 3-12.
12. Wacher, V. J.; Salphati, L.; Benet, L. Z. Active secretion andenterocytic drug metabolism barriers to drug absorption. Adv. DrugDeliv. Rev., 2001, 46(1-3), 89-102.
13. Wacher, V. J.; Silverman, J. A.; Zhang, Y.; Benet, L. Z. Role of Pglycoproteinand cytochrome P450 3A in limiting oral absorptionof peptides and peptidomimetics. J. Pharm. Sci., 1998, 87(11),1322-1330.
14. Zhang, L.; Reynolds, K. S.; Zhao, P.; Huang, S. M. Druginteractions evaluation: an integrated part of risk assessment oftherapeutics. Toxicol. Appl. Pharmacol., 2010, 243(2), 134-145.
15. Thummel, K. E.; Wilkinson, G. R. In vitro and in vivo druginteractions involving human CYP3A. Annu. Rev. Pharmacol.Toxicol., 1998, 38, 389-430. (Pubitemid 28231501)
16. Williams, J. A.; Hyland, R.; Jones, B. C.; Smith, D. A.; Hurst, S.;Goosen, T. C.; Peterkin, V.; Koup, J. R.; Ball, S. E. Drug-druginteractions for UDP-glucuronosyltransferase substrates: apharmacokinetic explanation for typically observed low exposure(AUCi/AUC) ratios. Drug Metab. Dispos., 2004, 32(11), 1201-1208. (Pubitemid 39410902)
17. Wacher, V. J.; Wu, C. Y.; Benet, L. Z. Overlapping substratespecificities and tissue distribution of cytochrome P450 3A and Pglycoprotein:implications for drug delivery and activity in cancerchemotherapy. Mol Carcinog, 1995, 13(3), 129-134.
18. Wang, E.; Lew, K.; Barecki, M.; Casciano, C. N.; Clement, R. P.;Johnson, W. W. Quantitative distinctions of active site molecularrecognition by P-glycoprotein and cytochrome P450 3A4. Chem.Res. Toxicol., 2001, 14(12), 1596-1603. (Pubitemid 34016623)
19. Zhou, S. F. Drugs behave as substrates, inhibitors and inducers ofhuman cytochrome P450 3A4. Curr. Drug Metab., 2008, 9(4), 310-322.
20. Guengerich, F. P.; Martin, M. V.; Beaune, P. H.; Kremers, P.;Wolff, T.; Waxman, D. J. Characterization of rat and human livermicrosomal cytochrome P-450 forms involved in nifedipineoxidation, a prototype for genetic polymorphism in oxidative drugmetabolism. J. Biol. Chem., 1986, 261(11), 5051-5060. (Pubitemid 17204301)
21. Kaminsky, L. S.; Fasco, M. J. Small intestinal cytochromes P450.Crit. Rev. Toxicol., 1991, 21(6), 407-422.
22. Kaminsky, L. S.; Zhang, Q. Y. The small intestine as a xenobioticmetabolizingorgan. Drug Metab. Dispos., 2003, 31(12), 1520-1525.
23. Kolars, J. C.; Awni, W. M.; Merion, R. M.; Watkins, P. B. Firstpassmetabolism of cyclosporin by the gut. Lancet, 1991,338(8781), 1488-1490.
24. Kolars, J. C.; Lown, K. S.; Schmiedlin-Ren, P.; Ghosh, M.; Fang,C.; Wrighton, S. A.; Merion, R. M.; Watkins, P. B. CYP3A geneexpression in human gut epithelium. Pharmacogenetics, 1994,4(5), 247-259. (Pubitemid 24337433)
25. Kolars, J. C.; Schmiedlin-Ren, P.; Schuetz, J. D.; Fang, C.;Watkins, P. B. Identification of rifampin-inducible P450IIIA4(CYP3A4) in human small bowel enterocytes. J. Clin. Invest.,1992, 90(5), 1871-1878.
26. Mouly, S.; Paine, M. F. P-glycoprotein increases from proximal todistal regions of human small intestine. Pharm. Res., 2003, 20(10),1595-1599. (Pubitemid 37268274)
27. Paine, M. F.; Khalighi, M.; Fisher, J. M.; Shen, D. D.; Kunze, K.L.; Marsh, C. L.; Perkins, J. D.; Thummel, K. E. Characterizationof interintestinal and intraintestinal variations in human CYP3Adependentmetabolism. J. Pharmacol. Exp. Ther., 1997, 283(3),1552-1562. (Pubitemid 28016533)
28. Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y.; Guengerich, F.P. Interindividual variations in human liver cytochrome P-450enzymes involved in the oxidation of drugs, carcinogens and toxicchemicals: studies with liver microsomes of 30 Japanese and 30Caucasians. J. Pharmacol. Exp. Ther., 1994, 270(1), 414-423. (Pubitemid 24229655)
29. Thiebaut, F.; Tsuruo, T.; Hamada, H.; Gottesman, M. M.; Pastan,I.; Willingham, M. C. Cellular localization of the multidrugresistancegene product P-glycoprotein in normal human tissues.Proc. Natl. Acad. Sci. U S A, 1987, 84(21), 7735-7738.
30. Thummel, K. E.; O'Shea, D.; Paine, M. F.; Shen, D. D.; Kunze, K.L.; Perkins, J. D.; Wilkinson, G. R. Oral first-pass elimination ofmidazolam involves both gastrointestinal and hepatic CYP3Amediatedmetabolism. Clin. Pharmacol. Ther., 1996, 59(5), 491-502. (Pubitemid 26193889)
31. Watkins, P. B.; Wrighton, S. A.; Schuetz, E. G.; Molowa, D. T.;Guzelian, P. S. Identification of glucocorticoid-induciblecytochromes P-450 in the intestinal mucosa of rats and man. J.Clin. Invest., 1987, 80(4), 1029-1036. (Pubitemid 18075638)
32. Zhang, Q. Y.; Dunbar, D.; Ostrowska, A.; Zeisloft, S.; Yang, J.;Kaminsky, L. S. Characterization of human small intestinalcytochromes P-450. Drug Metab. Dispos., 1999, 27(7), 804-809. (Pubitemid 29297778)
33. Gotoh, Y.; Suzuki, H.; Kinoshita, S.; Hirohashi, T.; Kato, Y.;Sugiyama, Y. Involvement of an organic anion transporter(canalicular multispecific organic anion transporter/multidrugresistance-associated protein 2) in gastrointestinal secretion ofglutathione conjugates in rats. J. Pharmacol. Exp. Ther., 2000,292(1), 433-439. (Pubitemid 30026403)
34. Konig, J.; Nies, A. T.; Cui, Y.; Leier, I.; Keppler, D. Conjugateexport pumps of the multidrug resistance protein (MRP) family:localization, substrate specificity, and MRP2-mediated drugresistance. Biochim. Biophys. Acta, 1999, 1461(2), 377-394.
35. Suzuki, H.; Sugiyama, Y. Excretion of GSSG and glutathioneconjugates mediated by MRP1 and cMOAT/MRP2. Semin LiverDis., 1998, 18(4), 359-376. (Pubitemid 29011040)
36. Kondo, C.; Onuki, R.; Kusuhara, H.; Suzuki, H.; Suzuki, M.;Okudaira, N.; Kojima, M.; Ishiwata, K.; Jonker, J. W.; Sugiyama,Y. Lack of improvement of oral absorption of ME3277 by prodrugformation is ascribed to the intestinal efflux mediated by breastcancer resistant protein (BCRP/ABCG2). Pharm. Res., 2005, 22(4),613-618. (Pubitemid 40603259)
37. Okudaira, N.; Komiya, I.; Sugiyama, Y. Polarized efflux of monoanddiacid metabolites of ME3229, an ester-type prodrug of aglycoprotein IIb/IIIa receptor antagonist, in rat small intestine. J.Pharmacol. Exp. Ther., 2000, 295(2), 717-723.
38. Okudaira, N.; Tatebayashi, T.; Speirs, G. C.; Komiya, I.;Sugiyama, Y. A study of the intestinal absorption of an ester-typeprodrug, ME3229, in rats: active efflux transport as a cause of poorbioavailability of the active drug. J. Pharmacol. Exp. Ther., 2000,294(2), 580-587. (Pubitemid 30490832)
39. Benet, L. Z. The drug transporter-metabolism alliance: uncoveringand defining the interplay. Mol. Pharm., 2009, 6(6), 1631-1643.
40. Benet, L. Z.; Cummins, C. L.; Wu, C. Y. Unmasking the dynamicinterplay between efflux transporters and metabolic enzymes. Int.J. Pharm., 2004, 277(1-2), 3-9. (Pubitemid 38670415)
41. Cummins, C. L.; Jacobsen, W.; Benet, L. Z. Unmasking thedynamic interplay between intestinal P-glycoprotein and CYP3A4.J. Pharmacol. Exp. Ther., 2002, 300(3), 1036-1045. (Pubitemid 34165010)
42. Cummins, C. L.; Salphati, L.; Reid, M. J.; Benet, L. Z. In vivomodulation of intestinal CYP3A metabolism by P-glycoprotein:studies using the rat single-pass intestinal perfusion model. J.Pharmacol. Exp. Ther., 2003, 305(1), 306-314. (Pubitemid 36373865)
43. Cummins, C. L.; Wu, C. Y.; Benet, L. Z. Sex-related differences inthe clearance of cytochrome P450 3A4 substrates may be caused byP-glycoprotein. Clin. Pharmacol. Ther., 2002, 72(5), 474-489. (Pubitemid 36237718)
44. Gan, L. S.; Moseley, M. A.; Khosla, B.; Augustijns, P. F.;Bradshaw, T. P.; Hendren, R. W.; Thakker, D. R. CYP3A-likecytochrome P450-mediated metabolism and polarized efflux ofcyclosporin A in Caco-2 cells. Drug Metab. Dispos., 1996, 24(3),344-349.
45. Hochman, J. H.; Chiba, M.; Nishime, J.; Yamazaki, M.; Lin, J. H.Influence of P-glycoprotein on the transport and metabolism ofindinavir in Caco-2 cells expressing cytochrome P-450 3A4. J.Pharmacol. Exp. Ther., 2000, 292(1), 310-318. (Pubitemid 30026387)
46. Ito, K.; Kusuhara, H.; Sugiyama, Y. Effects of intestinal CYP3A4and P-glycoprotein on oral drug absorption - theoretical approach.Pharm. Res., 1999, 16(2), 225-231. (Pubitemid 29135126)
47. Paine, M. F.; Ludington, S. S.; Chen, M. L.; Stewart, P. W.; Huang,S. M.; Watkins, P. B. Do men and women differ in proximal smallintestinal CYP3A or P-glycoprotein expression? Drug Metab.Dispos., 2005, 33(3), 426-433. (Pubitemid 40279944)
48. Knight, B.; Troutman, M.; Thakker, D. R. Deconvoluting theeffects of P-glycoprotein on intestinal CYP3A: a major challenge.Curr. Opin. Pharmacol., 2006, 6(5), 528-532. (Pubitemid 44340667)
49. Pang, K. S.; Maeng, H. J.; Fan, J. Interplay of transporters andenzymes in drug and metabolite processing. Mol. Pharm., 2009,6(6), 1734-1755.
50. Fisher, J. M.; Wrighton, S. A.; Watkins, P. B.; Schmiedlin-Ren, P.;Calamia, J. C.; Shen, D. D.; Kunze, K. L.; Thummel, K. E. Firstpassmidazolam metabolism catalyzed by 1alpha,25-dihydroxyvitamin D3-modified Caco-2 cell monolayers. J. Pharmacol. Exp.Ther., 1999, 289(2), 1134-1142. (Pubitemid 29191276)
51. Johnson, B. M.; Charman, W. N.; Porter, C. J. Application ofcompartmental modeling to an examination of in vitro intestinalpermeability data: assessing the impact of tissue uptake, Pglycoprotein,and CYP3A. Drug Metab. Dispos., 2003, 31(9),1151-1160. (Pubitemid 37048287)
52. Sirianni, G. L.; Pang, K. S. Organ clearance concepts: newperspectives on old principles. J. Pharmacokinet. Biopharm., 1997,25(4), 449-470. (Pubitemid 28186446)
53. Tam, D.; Sun, H.; Pang, K. S. Influence of P-glycoprotein, transferclearances, and drug binding on intestinal metabolism in Caco-2cell monolayers or membrane preparations: a theoretical analysis.Drug Metab. Dispos., 2003, 31(10), 1214-1226. (Pubitemid 37152972)
54. Cummins, C. L.; Jacobsen, W.; Christians, U.; Benet, L. Z.CYP3A4-transfected Caco-2 cells as a tool for understandingbiochemical absorption barriers: studies with sirolimus andmidazolam. J. Pharmacol. Exp. Ther., 2004, 308(1), 143-155. (Pubitemid 38090712)
55. Otyepka, M.; Skopalik, J.; Anzenbacherova, E.; Anzenbacher, P.What common structural features and variations of mammalianP450s are known to date? Biochim. Biophys. Acta, 2007, 1770(3),376-389. (Pubitemid 46136748)
56. Williams, P. A.; Cosme, J.; Vinkovic, D. M.; Ward, A.; Angove, H.C.; Day, P. J.; Vonrhein, C.; Tickle, I. J.; Jhoti, H. Crystalstructures of human cytochrome P450 3A4 bound to metyraponeand progesterone. Science, 2004, 305(5684), 683-686. (Pubitemid 39006760)
57. Rendic, S. Summary of information on human CYP enzymes:human P450 metabolism data. Drug Metab. Rev., 2002, 34(1-2),83-448. (Pubitemid 34311090)
58. Yano, J. K.; Wester, M. R.; Schoch, G. A.; Griffin, K. J.; Stout, C.D.; Johnson, E. F. The structure of human microsomal cytochromeP450 3A4 determined by X-ray crystallography to 2.05-Aresolution. J. Biol. Chem., 2004, 279(37), 38091-38094. (Pubitemid 39295952)
59. Ekroos, M.; Sjogren, T. Structural basis for ligand promiscuity incytochrome P450 3A4. Proc. Natl. Acad. Sci. U S A, 2006,103(37), 13682-13687. (Pubitemid 44413967)
60. Harlow, G. R.; Halpert, J. R. Analysis of human cytochrome P4503A4 cooperativity: construction and characterization of a sitedirectedmutant that displays hyperbolic steroid hydroxylationkinetics. Proc. Natl. Acad. Sci. U S A, 1998, 95(12), 6636-6641. (Pubitemid 28278032)
61. Kenworthy, K. E.; Clarke, S. E.; Andrews, J.; Houston, J. B.Multisite kinetic models for CYP3A4: simultaneous activation andinhibition of diazepam and testosterone metabolism. Drug Metab.Dispos., 2001, 29(12), 1644-1651. (Pubitemid 33111598)
62. Korzekwa, K. R.; Krishnamachary, N.; Shou, M.; Ogai, A.; Parise,R. A.; Rettie, A. E.; Gonzalez, F. J.; Tracy, T. S. Evaluation ofatypical cytochrome P450 kinetics with two-substrate models:evidence that multiple substrates can simultaneously bind tocytochrome P450 active sites. Biochemistry, 1998, 37(12), 4137-4147. (Pubitemid 28166435)
63. Shou, M.; Grogan, J.; Mancewicz, J. A.; Krausz, K. W.; Gonzalez,F. J.; Gelboin, H. V.; Korzekwa, K. R. Activation of CYP3A4:evidence for the simultaneous binding of two substrates in acytochrome P450 active site. Biochemistry, 1994, 33(21), 6450-6455. (Pubitemid 24189354)
64. Domanski, T. L.; Liu, J.; Harlow, G. R.; Halpert, J. R. Analysis offour residues within substrate recognition site 4 of humancytochrome P450 3A4: role in steroid hydroxylase activity andalpha-naphthoflavone stimulation. Arch. Biochem. Biophys., 1998,350(2), 223-232. (Pubitemid 28368647)
65. Khan, K. K.; He, Y. Q.; Domanski, T. L.; Halpert, J. R. Midazolamoxidation by cytochrome P450 3A4 and active-site mutants: anevaluation of multiple binding sites and of the metabolic pathwaythat leads to enzyme inactivation. Mol. Pharmacol., 2002, 61(3),495-506. (Pubitemid 34171915)
66. Stevens, J. C.; Domanski, T. L.; Harlow, G. R.; White, R. B.;Orton, E.; Halpert, J. R. Use of the steroid derivative RPR 106541in combination with site-directed mutagenesis for enhancedcytochrome P-450 3A4 structure/function analysis. J. Pharmacol.Exp. Ther., 1999, 290(2), 594-602. (Pubitemid 29344551)
67. Scott, E. E.; Halpert, J. R. Structures of cytochrome P450 3A4.Trends Biochem. Sci., 2005, 30(1), 5-7. (Pubitemid 40093733)
68. Rosenberg, M. F.; Callaghan, R.; Ford, R. C.; Higgins, C. F.Structure of the multidrug resistance P-glycoprotein to 2.5 nmresolution determined by electron microscopy and image analysis.J. Biol. Chem., 1997, 272(16), 10685-10694. (Pubitemid 27181079)
69. Rosenberg, M. F.; Callaghan, R.; Modok, S.; Higgins, C. F.; Ford,R. C. Three-dimensional structure of P-glycoprotein: thetransmembrane regions adopt an asymmetric configuration in thenucleotide-bound state. J. Biol. Chem., 2005, 280(4), 2857-2862. (Pubitemid 40189394)
70. Rosenberg, M. F.; Kamis, A. B.; Callaghan, R.; Higgins, C. F.;Ford, R. C. Three-dimensional structures of the mammalianmultidrug resistance P-glycoprotein demonstrate majorconformational changes in the transmembrane domains uponnucleotide binding. J. Biol. Chem., 2003, 278(10), 8294-8299. (Pubitemid 36800576)
71. Chang, G. Structure of MsbA from Vibrio cholera: a multidrugresistance ABC transporter homolog in a closed conformation. J.Mol. Biol., 2003, 330(2), 419-430. (Pubitemid 36773713)
72. Chang, G.; Roth, C. B. Structure of MsbA from E. coli: a homologof the multidrug resistance ATP binding cassette (ABC)transporters. Science, 2001, 293(5536), 1793-1800. (Pubitemid 32845770)
73. Reyes, C. L.; Chang, G. Structure of the ABC transporter MsbA incomplex with ADP.vanadate and lipopolysaccharide. Science,2005, 308(5724), 1028-1031. (Pubitemid 40664414)
74. Chang, G.; Roth, C. B.; Reyes, C. L.; Pornillos, O.; Chen, Y. J.;Chen, A. P. Retraction. Science, 2006, 314(5807), 1875.
75. Dawson, R. J.; Locher, K. P. Structure of a bacterial multidrugABC transporter. Nature, 2006, 443(7108), 180-185.
76. Dawson, R. J.; Locher, K. P. Structure of the multidrug ABCtransporter Sav1866 from Staphylococcus aureus in complex withAMP-PNP. FEBS Lett., 2007, 581(5), 935-938. (Pubitemid 46282725)
77. Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.;Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L.; Chang, G.Structure of P-glycoprotein reveals a molecular basis for polyspecificdrug binding. Science, 2009, 323(5922), 1718-1722.
78. Loo, T. W.; Bartlett, M. C.; Clarke, D. M. Transmembrane segment7 of human P-glycoprotein forms part of the drug-binding pocket.Biochem. J., 2006, 399(2), 351-359. (Pubitemid 44570297)
79. Loo, T. W.; Clarke, D. M. Identification of residues in the drugbindingsite of human P-glycoprotein using a thiol-reactivesubstrate. J. Biol. Chem., 1997, 272(51), 31945-31948. (Pubitemid 28011858)
80. Raviv, Y.; Pollard, H. B.; Bruggemann, E. P.; Pastan, I.;Gottesman, M. M. Photosensitized labeling of a functionalmultidrug transporter in living drug-resistant tumor cells. J. Biol.Chem., 1990, 265(7), 3975-3980.
81. Afzelius, L.; Arnby, C. H.; Broo, A.; Carlsson, L.; Isaksson, C.;Jurva, U.; Kjellander, B.; Kolmodin, K.; Nilsson, K.; Raubacher,F.; Weidolf, L. State-of-the-art tools for computational site ofmetabolism predictions: comparative analysis, mechanistical insights, and future applications. Drug Metab. Rev., 2007, 39(1),61-86.
82. Crivori, P.; Poggesi, I. Computational approaches for predictingCYP-related metabolism properties in the screening of new drugs.Eur. J. Med. Chem., 2006, 41(7), 795-808. (Pubitemid 44015977)
83. Czodrowski, P.; Kriegl, J. M.; Scheuerer, S.; Fox, T.Computational approaches to predict drug metabolism. ExpertOpin. Drug Metab. Toxicol., 2009, 5(1), 15-27.
84. de Graaf, C.; Vermeulen, N. P.; Feenstra, K. A. Cytochrome p450in silico: an integrative modeling approach. J. Med. Chem., 2005,48(8), 2725-2755. (Pubitemid 40548088)
85. de Groot, M. J. Designing better drugs: predicting cytochromeP450 metabolism. Drug Discov. Today, 2006, 11(13-14), 601-606.
86. Lewis, D. F.; Ito, Y. Human CYPs involved in drug metabolism:structures, substrates and binding affinities. Expert Opin. DrugMetab. Toxicol., 2010, 6(6), 661-674.
87. Stjernschantz, E.; Vermeulen, N. P.; Oostenbrink, C.Computational prediction of drug binding and rationalisation ofselectivity towards cytochromes P450. Expert Opin. Drug Metab.Toxicol., 2008, 4(5), 513-527. (Pubitemid 351890736)
88. Demel, M. A.; Schwaha, R.; Kramer, O.; Ettmayer, P.; Haaksma,E. E.; Ecker, G. F. In silico prediction of substrate properties forABC-multidrug transporters. Expert Opin. Drug Metab. Toxicol.,2008, 4(9), 1167-1180.
89. Ha, S. N.; Hochman, J.; Sheridan, R. P. Mini review on molecularmodeling of P-glycoprotein (Pgp). Curr. Top. Med. Chem., 2007,7(15), 1525-1529. (Pubitemid 47618065)
90. Mensch, J.; Oyarzabal, J.; Mackie, C.; Augustijns, P. In vivo, invitro and in silico methods for small molecule transfer across theBBB. J. Pharm. Sci., 2009, 98(12), 4429-4468.
91. Seeger, M. A.; van Veen, H. W. Molecular basis of multidrugtransport by ABC transporters. Biochim. Biophys. Acta, 2009,1794(5), 725-737.
92. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R.Development and validation of a genetic algorithm for flexibledocking. J. Mol. Biol., 1997, 267(3), 727-748. (Pubitemid 27170693)
93. Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic,J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.;Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: a newapproach for rapid, accurate docking and scoring. 1. Method andassessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749. (Pubitemid 38380917)
94. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R.K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDockTools4:Automated docking with selective receptor flexibility. J. Comput.Chem., 2009, 30(16), 2785-2791.
95. Ewing, T. J.; Makino, S.; Skillman, A. G.; Kuntz, I. D. DOCK 4.0:search strategies for automated molecular docking of flexiblemolecule databases. J. Comput. Aided Mol. Des., 2001, 15(5), 411-428. (Pubitemid 32452109)
96. De Rienzo, F.; Fanelli, F.; Menziani, M. C.; De Benedetti, P. G.Theoretical investigation of substrate specificity for cytochromesP450 IA2, P450 IID6 and P450 IIIA4. J. Comput. Aided Mol. Des.,2000, 14(1), 93-116. (Pubitemid 30103825)
97. Teixeira, V. H.; Ribeiro, V.; Martel, P. J. Analysis of bindingmodes of ligands to multiple conformations of CYP3A4. Biochim.Biophys. Acta, 2010, 1804(10), 2036-2045.
98. Ecker, G. F.; Stockner, T.; Chiba, P. Computational models forprediction of interactions with ABC-transporters. Drug Discov.Today, 2008, 13(7-8), 311-317.
99. Ward, A.; Reyes, C. L.; Yu, J.; Roth, C. B.; Chang, G. Flexibilityin the ABC transporter MsbA: Alternating access with a twist.Proc. Natl. Acad. Sci. U S A, 2007, 104(48), 19005-19010.
100. Becker, J. P.; Depret, G.; Van Bambeke, F.; Tulkens, P. M.;Prevost, M. Molecular models of human P-glycoprotein in twodifferent catalytic states. BMC Struct. Biol., 2009, 9, 3.
101. Globisch, C.; Pajeva, I. K.; Wiese, M. Identification of putativebinding sites of P-glycoprotein based on its homology model.Chem.Med.Chem., 2008, 3(2), 280-295.
102. O'Mara, M. L.; Tieleman, D. P. P-glycoprotein models of the apoand ATP-bound states based on homology with Sav1866 andMalK. FEBS Lett., 2007, 581(22), 4217-4222. (Pubitemid 47301854)
103. Ravna, A. W.; Sylte, I.; Sager, G. Molecular model of the outwardfacing state of the human P-glycoprotein (ABCB1), andcomparison to a model of the human MRP5 (ABCC5). Theor. Biol.Med. Model, 2007, 4, 33.
104. Ravna, A. W.; Sylte, I.; Sager, G. Binding site of ABC transporterhomology models confirmed by ABCB1 crystal structure. Theor.Biol. Med. Model, 2009, 6, 20.
105. Pajeva, I. K.; Globisch, C.; Wiese, M. Comparison of the inwardandoutward-open homology models and ligand binding of humanP-glycoprotein. FEBS J., 2009, 276(23), 7016-7026.
106. Terfloth, L.; Bienfait, B.; Gasteiger, J. Ligand-based models for theisoform specificity of cytochrome P450 3A4, 2D6, and 2C9substrates. J. Chem. Inf. Model, 2007, 47(4), 1688-1701. (Pubitemid 47210071)
107. Ekins, S.; Bravi, G.; Wikel, J. H.; Wrighton, S. A. Threedimensional- quantitative structure activity relationship analysis ofcytochrome P-450 3A4 substrates. J. Pharmacol. Exp. Ther., 1999,291(1), 424-433. (Pubitemid 29451619)
108. Wang, Y. H.; Li, Y.; Yang, S. L.; Yang, L. Classification ofsubstrates and inhibitors of P-glycoprotein using unsupervisedmachine learning approach. J. Chem. Inf. Model, 2005, 45(3), 750-757. (Pubitemid 40795178)
109. Huang, J.; Ma, G.; Muhammad, I.; Cheng, Y. Identifying Pglycoproteinsubstrates using a support vector machine optimizedby a particle swarm. J. Chem. Inf. Model, 2007, 47(4), 1638-1647. (Pubitemid 47210067)
110. Xue, Y.; Yap, C. W.; Sun, L. Z.; Cao, Z. W.; Wang, J. F.; Chen, Y.Z. Prediction of P-glycoprotein substrates by a support vectormachine approach. J. Chem. Inf. Comput. Sci., 2004, 44(4), 1497-1505.
111. Gombar, V. K.; Polli, J. W.; Humphreys, J. E.; Wring, S. A.;Serabjit-Singh, C. S. Predicting P-glycoprotein substrates by aquantitative structure-activity relationship model. J. Pharm. Sci.,2004, 93(4), 957-968. (Pubitemid 38420406)
112. Li, W. X.; Li, L.; Eksterowicz, J.; Ling, X. B.; Cardozo, M.Significance analysis and multiple pharmacophore models fordifferentiating P-glycoprotein substrates. J. Chem. Inf. Model,2007, 47(6), 2429-2438. (Pubitemid 350275107)
113. Garrigues, A.; Loiseau, N.; Delaforge, M.; Ferte, J.; Garrigos, M.;Andre, F.; Orlowski, S. Characterization of two pharmacophores onthe multidrug transporter P-glycoprotein. Mol. Pharmacol., 2002,62(6), 1288-1298. (Pubitemid 35403824)
114. Wang, E. J.; Casciano, C. N.; Clement, R. P.; Johnson, W. W. Twotransport binding sites of P-glycoprotein are unequal yetcontingent: initial rate kinetic analysis by ATP hydrolysisdemonstrates intersite dependence. Biochim. Biophys. Acta, 2000,1481(1), 63-74. (Pubitemid 30658082)
115. Raub, T. J. P-glycoprotein recognition of substrates andcircumvention through rational drug design. Mol. Pharm., 2006,3(1), 3-25. (Pubitemid 43331747)
116. Didziapetris, R.; Japertas, P.; Avdeef, A.; Petrauskas, A.Classification analysis of P-glycoprotein substrate specificity. J.Drug Target, 2003, 11(7), 391-406. (Pubitemid 38455825)
117. Seelig, A. A general pattern for substrate recognition by Pglycoprotein.Eur. J. Biochem., 1998, 251(1-2), 252-261. (Pubitemid 28081437)
118. Sawada, G. A.; Barsuhn, C. L.; Lutzke, B. S.; Houghton, M. E.;Padbury, G. E.; Ho, N. F.; Raub, T. J. Increased lipophilicity andsubsequent cell partitioning decrease passive transcellular diffusionof novel, highly lipophilic antioxidants. J. Pharmacol. Exp. Ther.,1999, 288(3), 1317-1326. (Pubitemid 29254173)
119. Raub, T. J.; Lutzke, B. S.; Andrus, P. K.; Sawada, G. A.; Staton, B.A. Early Preclinical Evaluation of Brain Exposure in Support of HitIdentification and Lead Optimization. In: Optimizing the "Drug-Like" Properties of Leads in Drug Discovery, Borchardt, R. T.;Hageman, M. J.; Kerns, E. H.; Stevens, J. L.; Thakker, D. R., Eds.Springer: New York, NY, 2006; Vol. IV, pp 355-410.
120. Kalvass, J. C.; Tess, D. A.; Giragossian, C.; Linhares, M. C.;Maurer, T. S. Influence of Microsomal Concentration on ApparentIntrinsic Clearance: Implications for Scaling in Vitro Data. DrugMetabolism and Disposition, 2001, 29(10), 1332-1336. (Pubitemid 32896583)
121. Obach, R. S. Prediction of Human Clearance of Twenty-NineDrugs from Hepatic Microsomal Intrinsic Clearance Data: AnExamination of In Vitro Half-Life Approach and NonspecificBinding to Microsomes. Drug Metabolism and Disposition, 1999,27(11), 1350-1359.
122. Gasser, R.; Funk, C.; Matzinger, P.; Klemisch, W.; Viger-Chougnet, A. Use of Transgenic Cell Lines in Mechanistic Studiesof Drug Metabolism. Toxicology in Vitro, 1999, 13(4-5), 625-632. (Pubitemid 29354188)
123. Laine, R. Metabolic stability: main enzymes involved and besttools to assess it. Current Drug Metabolism, 2008, 9(9), 921-927.
124. Hidalgo IJ, R. T., Borchardt RT. Characterization of the humancolon carcinoma cell line (Caco-2) as a model system for intestinalepithelial permeability. Gastroenterology, 1989, 96(3), 736-749. (Pubitemid 19057595)
125. Artursson, P. Epithelial transport of drugs in cell culture. I: Amodel for studying the passive diffusion of drugs over intestinalabsorbtive (Caco-2) cells. J. of Pharm. Sci., 1990, 79(6), 476-482. (Pubitemid 20221389)
126. Pastan, I.; Gottesman, M. M.; Ueda, K.; Lovelace, E.; Rutherford,A. V.; Willingham, M. C. A retrovirus carrying an MDR1 cDNAconfers multidrug resistance and polarized expression of Pglycoproteinin MDCK cells. Proceedings of the National Academyof Sciences of the United States of America, 1988, 85(12), 4486-4490.
127. Nielsen, R. Characterization of a kidney proximal tubule cell line,LLC-PK1, expressing endocytic active megalin. J. Am. Soc.Nephrol., 1998, 9, 1767-1776. (Pubitemid 28443473)
128. Polli, J. W.; Wring, S. A.; Humphreys, J. E.; Huang, L.; Morgan, J.B.; Webster, L. O.; Serabjit-Singh, C. S. Rational use of in vitro Pglycoproteinassays in drug discovery. J. Pharmacol. Exp. Ther.,2001, 299(2), 620-628. (Pubitemid 32979675)
129. Zhang, Y.; Benet, L. Z. Characterization of P-glycoproteinMediated Transport of K02, a Novel Vinylsulfone PeptidomimeticCysteine Protease Inhibitor, Across MDR1-MDCK and Caco-2Cell Monolayers. Pharm. Res., 1998, 15(10), 1520-1524. (Pubitemid 28465736)
130. Tiberghien, F.; Loor, F. Ranking of P-glycoprotein substrates andinhibitors by a calcein-AM fluorometry screening assay.Anticancer Drugs, 1996, 7(5), 568-578. (Pubitemid 26276348)
131. Cummins, C. L.; Mangravite, L. M.; Benet, L. Z. Characterizingthe Expression of CYP3A4 and Efflux Transporters (P-gp, MRP1,and MRP2) in CYP3A4-Transfected Caco-2 Cells After Inductionwith Sodium Butyrate and the Phorbol Ester 12-OTetradecanoylphorbol-13-Acetate. Pharm. Res., 2001, 18(8), 1102-1109. (Pubitemid 32900394)
132. Prueksaritanont, T.; Gorham, L. M.; Hochman, J. H.; Tran, L. O.;Vyas, K. P. Comparative studies of drug-metabolizing enzymes indog, monkey, and human small intestines, and in Caco-2 cells.Drug Metab. and Dispos., 1996, 24(6), 634-642. (Pubitemid 26170714)
133. Schmiedlin-Ren, P.; Thummel, K. E.; Fisher, J. M.; Paine, M. F.;Lown, K. S.; Watkins, P. B. Expression of Enzymatically ActiveCYP3A4 by Caco-2 Cells Grown on Extracellular Matrix-CoatedPermeable Supports in the Presence of 1α,25-DihydroxyvitaminD3. Molecular Pharmacology, 1997, 51(5), 741-754. (Pubitemid 27224679)
134. Crespi, C. L.; Penman, B. W.; Hu, M. Development of Caco-2Cells Expressing High Levels of cDNA-Derived CytochromeP4503A4. Pharm. Res., 1996, 13(11), 1635-1641. (Pubitemid 26426885)
135. Volpe, D. A. Variability in Caco-2 and MDCK cell-based intestinalpermeability assays. J. Pharm. Sci., 2008, 97(2), 712-725. (Pubitemid 351293876)
136. Hu, M.; Li, Y.; Davitt, C.; Huang, S.-M.; Thummel, K.; Penman,B.; Crespi, C. Transport and Metabolic Characterization of Caco-2Cells Expressing CYP3A4 and CYP3A4 Plus Oxidoreductase.Pharm. Res., 1999, 16(9), 1352-1359. (Pubitemid 29449370)
137. Brimer, C.; Dalton, J. T.; Zhu, Z.; Schuetz, J.; Yasuda, K.; Vanin,E.; Relling, M. V.; Lu, Y.; Schuetz, E. G. Creation of PolarizedCells Coexpressing CYP3A4, NADPH Cytochrome P450Reductase and MDR1/P-glycoprotein. Pharm. Res., 2000, 17(7),803-810. (Pubitemid 30666960)
138. Raeissi, S. D.; Hidalgo, I. J.; Segura-Aguilar, J.; Artursson, P.Interplay Between CYP3A-Mediated Metabolism and PolarizedEfflux of Terfenadine and Its Metabolites in Intestinal EpithelialCaco-2 (TC7) Cell Monolayers. Pharm. Res., 1999, 16(5), 625-632. (Pubitemid 29227089)
139. Swift, B.; Pfeifer, N. D.; Brouwer, K. L. R. Sandwich- culturedhepatocytes: an in vitro model to evaluate hepatobiliary transporterbaseddrug interactions and hepatotoxicity. Drug Metab.Rev., 2010,42(3), 446-471.
140. Turncliff, R. Z.; Hoffmaster, K. A.; Kalvass, J. C.; Pollack, G. M.;Brouwer, K. L. Hepatobiliary disposition of a drug/metabolite pair:Comprehensive pharmacokinetic modeling in sandwich-culturedrat hepatocytes. J. Pharmacol. Exp. Ther., 2006, 318(2), 881-889. (Pubitemid 44061264)
141. Annaert, P. P.; Turncliff, R. Z.; Booth, C. L.; Thakker, D. R.;Brouwer, K. L. R. P-Glycoprotein-Mediated In Vitro BiliaryExcretion in Sandwich-Cultured Rat Hepatocytes. Drug Metab.and Dispos., 2001, 29(10), 1277-1283. (Pubitemid 32896576)
142. Tamura, S.; Tokunaga, Y.; Ibuki, R.; Amidon, G. L.; Sezaki, H.;Yamashita, S. The site-specific transport and metabolism oftacrolimus in rat small
143. Tamura, S.; Ohike, A.; Ibuki, R.; Amidon, G. L.; Yamashita, S.Tacrolimus is a class II low-solubility high-permeability drug: theeffect of P-glycoprotein efflux on regional permeability oftacrolimus in rats. J. Pharm. Sci., 2002, 91(3), 719-729. (Pubitemid 34639635)
144. Iida, A.; Tomita, M.; Hayashi, M. Regional difference in Pglycoproteinfunction in rat intestine. Drug Metab. Pharmacokinet.,2005, 20(2), 100-106.
145. Naud, J.; Michaud, J.; Boisvert, C.; Desbiens, K.; Leblond, F. A.;Mitchell, A.; Jones, C.; Bonnardeaux, A.; Pichette, V. Downregulationof intestinal drug transporters in chronic renal failure inrats. J. Pharmacol. Exp. Ther., 2007, 320(3), 978-985. (Pubitemid 46294060)
146. Kalitsky-Szirtes, J.; Shayeganpour, A.; Brocks, D. R.; Piquette-Miller, M. Suppression of drug-metabolizing enzymes and effluxtransporters in the intestine of endotoxin-treated rats. Drug Metab.Dispos., 2004, 32(1), 20-27. (Pubitemid 38112531)
147. Shayeganpour, A.; Korashy, H.; Patel, J. P.; El-Kadi, A. O.;Brocks, D. R. The impact of experimental hyperlipidemia on thedistribution and metabolism of amiodarone in rat. Int. J. Pharm.,2008, 361(1-2), 78-86.
148. Choi, Y. H.; Lee, I.; Lee, M. G. Effects of cysteine on metforminpharmacokinetics in rats with protein-calorie malnutrition: partialrestoration of some parameters to control levels. J. Pharm.Pharmacol., 2008, 60(2), 153-161. (Pubitemid 351211830)
149. Fradette, C.; Batonga, J.; Teng, S.; Piquette-Miller, M.; du Souich,P. Animal models of acute moderate hypoxia are associated with adown-regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and upregulationof CYP3A6 and P-glycoprotein in liver. Drug Metab.Dispos., 2007, 35(5), 765-771. (Pubitemid 46641547)
150. Yoshinari, K.; Takagi, S.; Yoshimasa, T.; Sugatani, J.; Miwa, M.Hepatic CYP3A expression is attenuated in obese mice fed a highfatdiet. Pharm. Res., 2006, 23(6), 1188-1200. (Pubitemid 43946141)
151. Yoshinari, K.; Takagi, S.; Sugatani, J.; Miwa, M. Changes in theexpression of cytochromes P450 and nuclear receptors in the liverof genetically diabetic db/db mice. Biol. Pharm. Bull., 2006, 29(8),1634-1638. (Pubitemid 44166365)
152. Projean, D.; Dautrey, S.; Vu, H. K.; Groblewski, T.; Brazier, J. L.;Ducharme, J. Selective downregulation of hepatic cytochromeP450 expression and activity in a rat model of inflammatory pain.Pharm. Res., 2005, 22(1), 62-70. (Pubitemid 40558147)
153. Cui, X.; Kalsotra, A.; Robida, A. M.; Matzilevich, D.; Moore, A.N.; Boehme, C. L.; Morgan, E. T.; Dash, P. K.; Strobel, H. W.Expression of cytochromes P450 4F4 and 4F5 in infection andinjury models of inflammation. Biochim. Biophys. Acta, 2003,1619(3), 325-331. (Pubitemid 36160610)
154. Kim, J. S.; Mitchell, S.; Kijek, P.; Tsume, Y.; Hilfinger, J.;Amidon, G. L. The suitability of an in situ perfusion model forpermeability determinations: utility for BCS class I biowaiverrequests. Mol. Pharm., 2006, 3(6), 686-694. (Pubitemid 46087485)
155. Zhang, Q. Y.; Wikoff, J.; Dunbar, D.; Kaminsky, L.Characterization of rat small intestinal cytochrome P450composition and inducibility. Drug Metab. Dispos., 1996, 24(3),322-328. (Pubitemid 26087086)
156. Takara, K.; Ohnishi, N.; Horibe, S.; Yokoyama, T. Expressionprofiles of drug-metabolizing enzyme CYP3A and drug effluxtransporter multidrug resistance 1 subfamily mRNAS in smallintestine. Drug Metab. Dispos., 2003, 31(10), 1235-1239. (Pubitemid 37152974)
157. Matsubara, T.; Kim, H. J.; Miyata, M.; Shimada, M.; Nagata, K.;Yamazoe, Y. Isolation and characterization of a new majorintestinal CYP3A form, CYP3A62, in the rat. J. Pharmacol. Exp.Ther., 2004, 309(3), 1282-1290. (Pubitemid 38669720)
158. Jin, M.; Shimada, T.; Yokogawa, K.; Nomura, M.; Ishizaki, J.;Piao, Y.; Kato, Y.; Tsuji, A.; Miyamoto, K. Site-dependentcontributions of P-glycoprotein and CYP3A to cyclosporin Aabsorption, and effect of dexamethasone in small intestine of mice.Biochem. Pharmacol., 2006, 72(8), 1042-1050. (Pubitemid 44374466)
159. Emoto, C.; Yamazaki, H.; Yamasaki, S.; Shimada, N.; Nakajima,M.; Yokoi, T. Characterization of cytochrome P450 enzymesinvolved in drug oxidations in mouse intestinal microsomes.Xenobiotica, 2000, 30(10), 943-953.
160. Cao, X.; Gibbs, S. T.; Fang, L.; Miller, H. A.; Landowski, C. P.;Shin, H. C.; Lennernas, H.; Zhong, Y.; Amidon, G. L.; Yu, L. X.;Sun, D. Why is it challenging to predict intestinal drug absorptionand oral bioavailability in human using rat model. Pharm. Res.,2006, 23(8), 1675-1686. (Pubitemid 44200529)
161. Paine, M. F.; Hart, H. L.; Ludington, S. S.; Haining, R. L.; Rettie,A. E.; Zeldin, D. C. The human intestinal cytochrome P450 "pie".Drug Metab. Dispos., 2006, 34(5), 880-886.
162. Zhang, Q. Y.; Dunbar, D.; Kaminsky, L. S. Characterization ofmouse small intestinal cytochrome P450 expression. Drug Metab.Dispos., 2003, 31(11), 1346-1351. (Pubitemid 37310323)
163. Shin, H. C.; Kim, H. R.; Cho, H. J.; Yi, H.; Cho, S. M.; Lee, D. G.;El-Aty, A. M.; Kim, J. S.; Sun, D.; Amidon, G. L. Comparativegene expression of intestinal metabolizing enzymes. Biopharm.Drug Dispos., 2009, 30(8), 411-421.
164. Nagata, K.; Ogino, M.; Shimada, M.; Miyata, M.; Gonzalez, F. J.;Yamazoe, Y. Structure and expression of the rat CYP3A1 gene:isolation of the gene (P450/6betaB) and characterization of therecombinant protein. Arch. Biochem. Biophys., 1999, 362(2), 242-253. (Pubitemid 29394353)
165. Kirita, S.; Matsubara, T. cDNA cloning and characterization of anovel member of steroid-induced cytochrome P450 3A in rats.Arch. Biochem. Biophys., 1993, 307(2), 253-258. (Pubitemid 24001560)
166. Gushchin, G. V.; Gushchin, M. I.; Gerber, N.; Boyd, R. T. A novelcytochrome P450 3A isoenzyme in rat intestinal microsomes.Biochem. Biophys. Res. Commun., 1999, 255(2), 394-398. (Pubitemid 29292270)
167. Gonzalez, F. J.; Song, B. J.; Hardwick, J. P. Pregnenolone 16alpha-carbonitrile-inducible P-450 gene family: gene conversionand differential regulation. Mol. Cell Biol., 1986, 6(8), 2969-2976. (Pubitemid 17190839)
168. Gonzalez, F. J.; Nebert, D. W.; Hardwick, J. P.; Kasper, C. B.Complete cDNA and protein sequence of a pregnenolone 16 alphacarbonitrile-induced cytochrome P-450. A representative of a newgene family. J. Biol. Chem., 1985, 260(12), 7435-7441. (Pubitemid 15063019)
169. Lindell, M.; Lang, M.; Lennernas, H. Expression of genes encodingfor drug metabolising cytochrome P450 enzymes and Pglycoproteinin the rat small intestine; comparison to the liver. Eur.J. Drug Metab. Pharmacokinet., 2003, 28(1), 41-48. (Pubitemid 36505825)
170. Mei, Q.; Richards, K.; Strong-Basalyga, K.; Fauty, S. E.; Taylor,A.; Yamazaki, M.; Prueksaritanont, T.; Lin, J. H.; Hochman, J.Using real-time quantitative TaqMan RT-PCR to evaluate the roleof dexamethasone in gene regulation of rat P-glycoproteinsmdr1a/1b and cytochrome P450 3A1/2. J. Pharm. Sci., 2004,93(10), 2488-2496. (Pubitemid 39319432)
171. Walters, H. C.; Craddock, A. L.; Fusegawa, H.; Willingham, M. C.;Dawson, P. A. Expression, transport properties, and chromosomallocation of organic anion transporter subtype 3. Am .J. Physiol.Gastrointest. Liver Physiol., 2000, 279(6), G1188-1200.
172. Troutman, L., Gan and Thakker The role of p-glycoprotein in drugdisposition: Significance to drug development. In:Drugs and thePharmaceutical Sciences 116: Drug-Drug Interactions , A.D., R.,Ed. Marcel-Decker: New York, NY, 2002; pp 295-357.
173. Stephens, R. H.; O'Neill, C. A.; Warhurst, A.; Carlson, G. L.;Rowland, M.; Warhurst, G. Kinetic profiling of P-glycoproteinmediateddrug efflux in rat and human intestinal epithelia. J.Pharmacol. Exp. Ther., 2001, 296(2), 584-591. (Pubitemid 32112489)
174. Shoji, T.; Suzuki, H.; Kusuhara, H.; Watanabe, Y.; Sakamoto, S.;Sugiyama, Y. ATP-dependent transport of organic anions intoisolated basolateral membrane vesicles from rat intestine. Am. J.Physiol. Gastrointest. Liver Physiol., 2004, 287(4), G749-756. (Pubitemid 39280432)
175. Shneider, B. L.; Dawson, P. A.; Christie, D. M.; Hardikar, W.;Wong, M. H.; Suchy, F. J. Cloning and molecular characterizationof the ontogeny of a rat ileal sodium-dependent bile acidtransporter. J. Clin. Invest., 1995, 95(2), 745-754.
176. Sakamoto, S.; Suzuki, H.; Kusuhara, H.; Sugiyama, Y. Effluxmechanism of taurocholate across the rat intestinal basolateralmembrane. Mol. Pharm., 2006, 3(3), 275-281. (Pubitemid 44021433)
177. Rost, D.; Mahner, S.; Sugiyama, Y.; Stremmel, W. Expression andlocalization of the multidrug resistance-associated protein 3 in ratsmall and large intestine. Am. J. Physiol. Gastrointest. LiverPhysiol., 2002, 282(4), G720-726. (Pubitemid 34651651)
178. Makhey, V. D.; Guo, A.; Norris, D. A.; Hu, P.; Yan, J.; Sinko, P. J.Characterization of the regional intestinal kinetics of drug efflux inrat and human intestine and in Caco-2 cells. Pharm. Res., 1998,15(8), 1160-1167. (Pubitemid 28401704)
179. Lu, H.; Klaassen, C. Tissue distribution and thyroid hormoneregulation of Pept1 and Pept2 mRNA in rodents. Peptides, 2006,27(4), 850-857.
180. Lazaridis, K. N.; Tietz, P.; Wu, T.; Kip, S.; Dawson, P. A.;LaRusso, N. F. Alternative splicing of the rat sodium/bile acidtransporter changes its cellular localization and transport properties.Proc. Natl. Acad. Sci. U S A, 2000, 97(20), 11092-11097.
181. Kip, N. S.; Lazaridis, K. N.; Masyuk, A. I.; Splinter, P. L.; Huebert,R. C.; LaRusso, N. F. Differential expression of cholangiocyte andileal bile acid transporters following bile acid supplementation anddepletion. World J. Gastroenterol., 2004, 10(10), 1440-1446. (Pubitemid 39206807)
182. Fricker, G.; Drewe, J.; Huwyler, J.; Gutmann, H.; Beglinger, C.Relevance of p-glycoprotein for the enteral absorption ofcyclosporin A: in vitro-in vivo correlation. Br. J. Pharmacol., 1996,118(7), 1841-1847. (Pubitemid 26252682)
183. Dietrich, C. G.; Geier, A.; Salein, N.; Lammert, F.; Roeb, E.; OudeElferink, R. P.; Matern, S.; Gartung, C. Consequences of bile ductobstruction on intestinal expression and function of multidrugresistance- associated protein 2. Gastroenterology, 2004, 126(4),1044-1053. (Pubitemid 38451176)
184. Cherrington, N. J.; Hartley, D. P.; Li, N.; Johnson, D. R.; Klaassen,C. D. Organ distribution of multidrug resistance proteins 1, 2, and 3(Mrp1, 2, and 3) mRNA and hepatic induction of Mrp3 byconstitutive androstane receptor activators in rats. J. Pharmacol.Exp. Ther., 2002, 300(1), 97-104. (Pubitemid 34028514)
185. Valenzuela, B.; Nacher, A.; Casabo, V. G.; Martin-Villodre, A. Theinfluence of active secretion processes on intestinal absorption ofsalbutamol in the rat. Eur. J. Pharm. Biopharm., 2001, 52(1), 31-37. (Pubitemid 32594787)
186. Su, S. F.; Huang, J. D. Inhibition of the intestinal digoxinabsorption and exsorption by quinidine. Drug Metab. Dispos.,1996, 24(2), 142-147.
187. Saitoh, H.; Hatakeyama, M.; Eguchi, O.; Oda, M.; Takada, M.Involvement of intestinal P-glycoprotein in the restrictedabsorption of methylprednisolone from rat small intestine. J.Pharm. Sci., 1998, 87(1), 73-75. (Pubitemid 28079264)
188. Saitoh, H.; Aungst, B. J. Possible involvement of multiple Pglycoprotein-mediated efflux systems in the transport of verapamiland other organic cations across rat intestine. Pharm. Res., 1995,12(9), 1304-1310.
189. Liu, S.; Tam, D.; Chen, X.; Pang, K. S. P-glycoprotein and anunstirred water layer barring digoxin absorption in the vascularlyperfused rat small intestine preparation: induction studies withpregnenolone-16alpha-carbonitrile. Drug Metab. Dispos., 2006,34(9), 1468-1479. (Pubitemid 44285387)
190. Kageyama, M.; Namiki, H.; Fukushima, H.; Ito, Y.; Shibata, N.;Takada, K. In vivo effects of cyclosporin A and ketoconazole onthe pharmacokinetics of representative substrates for Pglycoproteinand cytochrome P450 (CYP) 3A in rats. Biol. Pharm.Bull., 2005, 28(2), 316-322. (Pubitemid 40880016)
191. Carreno-Gomez, B.; Duncan, R. Everted rat intestinal sacs: a newmodel for the quantitation of P-glycoprotein mediated-efflux ofanticancer agents. Anticancer Res., 2000, 20(5A), 3157-3161.
192. Wang, E. J.; Lew, K.; Casciano, C. N.; Clement, R. P.; Johnson, W.W. Interaction of common azole antifungals with P glycoprotein.Antimicrob. Agents Chemother., 2002, 46(1), 160-165. (Pubitemid 34031618)
193. Johnson, B. M.; Chen, W.; Borchardt, R. T.; Charman, W. N.;Porter, C. J. A kinetic evaluation of the absorption, efflux, andmetabolism of verapamil in the autoperfused rat jejunum. J.Pharmacol. Exp. Ther., 2003, 305(1), 151-158. (Pubitemid 36373845)
194. Mudra, D. R.; Borchardt, R. T. Absorption barriers in the ratintestinal mucosa: 1. Application of an in situ perfusion model tosimultaneously assess drug permeation and metabolism. J. Pharm.Sci., 2010, 99(2), 982-998.
195. Lennernas, H. Animal data: the contributions of the UssingChamber and perfusion systems to predicting human oral drugdelivery in vivo. Adv. Drug Deliv. Rev., 2007, 59(11), 1103-1120. (Pubitemid 47615203)
196. Ho, P., Ni and Huguchi Advancing quantitative and mechanisticapproaches in interfacing gastrointestinal drug absorption studies inanimal and man. In:Animal Models for Oral Drug Deliver in Man:In situ and In vivo approaches , A, C. W. a. S., Ed. AphA/APSWashington, DC, 1983; pp 27-106.
197. Bronner, F.; Pansu, D.; Stein, W. D. An analysis of intestinalcalcium transport across the rat intestine. Am. J. Physiol., 1986,250(5 Pt 1), G561-569.
198. Bronner, F.; Yost, J. H. Saturable and nonsaturable copper andcalcium transport in mouse duodenum. Am. J. Physiol., 1985,249(1 Pt 1), G108-112. (Pubitemid 15231437)
199. Doluisio, J. T.; Billups, N. F.; Dittert, L. W.; Sugita, E. T.;Swintosky, J. V. Drug absorption. I. An in situ rat gut techniqueyielding realistic absorption rates. J. Pharm. Sci., 1969, 58(10),1196-1200.
200. Kavin, H.; Levin, N. W.; Stanley, M. M. Isolated perfused rat smallbowel - technic, studies of viability, glucose absorption. J. Appl.Physiol., 1967, 22(3), 604-611.
201. Griffiths, L. a. J. Models of drug absorption in situ and in consciousanimals. In:Models for Assessing Drug Absorption andMetabolism , Borchardt RT, S. P. a. W. G., Ed. Plenum Press: NewYork, New York, 1996; pp 67-82.
202. Grass, G. M.; Sweetana, S. A. In vitro measurement ofgastrointestinal tissue permeability using a new diffusion cell.Pharm. Res., 1988, 5(6), 372-376.
203. Acra, S. A.; Ghishan, F. K. Methods of investigating intestinaltransport. JPEN J Parenter. Enteral Nutr., 1991, 15(3), 93S-98S.
204. Jeong, E. J.; Liu, Y.; Lin, H.; Hu, M. In situ Single-Pass PerfusedRat Intestinal Model for Absorption and Metabolism. In:Otimization in Drug Discovery, Yan, Z.; Caldwell, G. W., Eds.Humana Press: Totowa, NJ, 2004; pp 65-76.
205. Rogers, J. D.; Ho, N. F.; Morozowich, W. Physical model approachto gastrointestinal absorption of prostaglandins III: In situ ratintestinal absorption of dinoprostone. J. Pharm. Sci., 1984, 73(11),1594-1599. (Pubitemid 15205540)
206. Sutton, S. C.; Rinaldi, M. T.; Vukovinsky, K. E. Comparison of thegravimetric, phenol red, and 14C-PEG-3350 methods to determinewater absorption in the rat single-pass intestinal perfusion model.AAPS Pharm.Sci., 2001, 3(3), E25.
207. Mols, R.; Brouwers, J.; Schinkel, A. H.; Annaert, P.; Augustijns, P.Intestinal perfusion with mesenteric blood sampling in wild-typeand knockout mice: evaluation of a novel tool in biopharmaceuticaldrug profiling. Drug Metab. Dispos., 2009, 37(6), 1334-1337.
208. Brouwers, J.; Mols, R.; Annaert, P.; Augustijns, P. Validation of adifferential in situ perfusion method with mesenteric bloodsampling in rats for intestinal drug interaction profiling. Biopharm.Drug Dispos., 2010, 31(5-6), 278-285.
209. Xia, C. Q.; Milton, M. N.; Gan, L. S. Evaluation of drugtransporterinteractions using in vitro and in vivo models. Curr.Drug Metab., 2007, 8(4), 341-363. (Pubitemid 46780063)
210. Hu, Y.; Smith, D. E.; Ma, K.; Jappar, D.; Thomas, W.; Hillgren, K.M. Targeted disruption of peptide transporter Pept1 gene in micesignificantly reduces dipeptide absorption in intestine. Mol.Pharm., 2008, 5(6), 1122-1130.
211. Adachi, Y.; Suzuki, H.; Schinkel, A. H.; Sugiyama, Y. Role ofbreast cancer resistance protein (Bcrp1/Abcg2) in the extrusion ofglucuronide and sulfate conjugates from enterocytes to intestinallumen. Mol. Pharmacol., 2005, 67(3), 923-928. (Pubitemid 40365339)
212. Holmstock, N.; Mols, R.; Annaert, P.; Augustijns, P. In situintestinal perfusion in knockout mice demonstrates inhibition ofintestinal p-glycoprotein by ritonavir causing increased darunavirabsorption. Drug Metab. Dispos., 2010, 38(9), 1407-1410.
213. Wrighton, S. A.; Stevens, J. C. The human hepatic cytochromesP450 involved in drug metabolism. Crit. Rev. Toxicol., 1992, 22(1),1-21.
214. Ryan, D. E.; Levin, W. Purification and characterization of hepaticmicrosomal cytochrome P-450. Pharmacol. Ther., 1990, 45(2),153-239. (Pubitemid 20008907)
215. Nebert, D. W.; Nelson, D. R. P450 gene nomenclature based onevolution. Methods Enzymol., 1991, 206, 3-11.
216. Guengerich, F. P. Characterization of human microsomalcytochrome P-450 enzymes. Annu. Rev. Pharmacol. Toxicol., 1989,29, 241-264. (Pubitemid 19107354)
217. Boobis, A. R.; Davies, D. S. Human cytochromes P-450.Xenobiotica, 1984, 14(1-2), 151-185.
218. Waxman, D. J.; Pampori, N. A.; Ram, P. A.; Agrawal, A. K.;Shapiro, B. H. Interpulse interval in circulating growth hormonepatterns regulates sexually dimorphic expression of hepaticcytochrome P450. Proc. Natl. Acad. Sci. U S A, 1991, 88(15),6868-6872. (Pubitemid 21915051)
219. Vuppugalla, R.; Shah, R. B.; Chimalakonda, A. P.; Fisher, C. W.;Mehvar, R. Microsomal cytochrome P450 levels and activities ofisolated rat livers perfused with albumin. Pharm. Res., 2003, 20(1),81-88. (Pubitemid 36152921)
220. Hughes, C. M.; Swanton, J. G.; Collier, P. S. Cyclosporin A anderythromycin: a study of a drug interaction in the in situ perfusedrat liver model. Biopharm. Drug Dispos., 1993, 14(7), 615-625. (Pubitemid 23303547)
221. Hughes, C. M.; Swanton, J. G.; Collier, P. S. The effect of threeH2-receptor antagonists on the disposition of midazolam in the ratin-situ perfused liver model. J. Pharm. Pharmacol., 1994, 46(12),1029-1031.
222. Dostalek, M.; Pistovcakova, J.; Jurica, J.; Tomandl, J.; Linhart, I.;Sulcova, A.; Hadasova, E. Effect of St John's wort (Hypericumperforatum) on cytochrome P-450 activity in perfused rat liver. LifeSci., 2005, 78(3), 239-244. (Pubitemid 41570192)
223. Komura, H.; Iwaki, M. Species differences in in vitro and in vivosmall intestinal metabolism of CYP3A substrates. J. Pharm. Sci.,2008, 97(5), 1775-1800.
224. Aiba, T.; Takehara, Y.; Okuno, M.; Hashimoto, Y. Poor correlationbetween intestinal and hepatic metabolic rates of CYP3A4substrates in rats. Pharm. Res., 2003, 20(5), 745-748. (Pubitemid 36515306)
225. Huang, L.; Wring, S. A.; Woolley, J. L.; Brouwer, K. R.; Serabjit-Singh, C.; Polli, J. W. Induction of P-glycoprotein and cytochromeP450 3A by HIV protease inhibitors. Drug Metab. Dispos., 2001,29(5), 754-760. (Pubitemid 32374579)
226. Hartley, D. P.; Dai, X.; He, Y. D.; Carlini, E. J.; Wang, B.; Huskey,S. E.; Ulrich, R. G.; Rushmore, T. H.; Evers, R.; Evans, D. C.Activators of the rat pregnane X receptor differentially modulatehepatic and intestinal gene expression. Mol. Pharmacol., 2004,65(5), 1159-1171. (Pubitemid 38543487)
227. Eeckhoudt, S. L.; Horsmans, Y.; Verbeeck, R. K. Differentialinduction of midazolam metabolism in the small intestine and liverby oral and intravenous dexamethasone pretreatment in rat.Xenobiotica, 2002, 32(11), 975-984. (Pubitemid 35347005)
228. Liu, Y.; Huang, L.; Hoffman, T.; Gosland, M.; Vore, M. MDR1substrates/modulators protect against beta-estradiol-17beta- Dglucuronidecholestasis in rat liver. Cancer Res., 1996, 56(21),4992-4997. (Pubitemid 26374440)
229. Smit, J. W.; Duin, E.; Steen, H.; Oosting, R.; Roggeveld, J.; Meijer,D. K. Interactions between P-glycoprotein substrates and othercationic drugs at the hepatic excretory level. Br. J. Pharmacol.,1998, 123(3), 361-370. (Pubitemid 28059704)
230. Delle Monache, M. D.; Gigliozzi, A.; Benedetti, A.; Marucci, L.;Bini, A.; Francia, C.; Papa, E.; Di Cosimo, E.; Fraioli, F.; Jezequel,A. M.; Alvaro, D. Effect of pharmacological modulation of liver Pglycoproteinson cyclosporin A biliary excretion and cholestasis: astudy in isolated perfused rat liver. Dig. Dis. Sci., 1999, 44(11),2196-2204.
231. Schinkel, A. H.; Mayer, U.; Wagenaar, E.; Mol, C. A.; vanDeemter, L.; Smit, J. J.; van der Valk, M. A.; Voordouw, A. C.;Spits, H.; van Tellingen, O.; Zijlmans, J. M.; Fibbe, W. E.; Borst,P. Normal viability and altered pharmacokinetics in mice lackingmdr1-type (drug-transporting) P-glycoproteins. Proc. Natl. Acad.Sci. U S A, 1997, 94(8), 4028-4033. (Pubitemid 27180493)
232. Brouwer, K. L. a. T. Isolated Perfused Liver. In: Models forAssessing Drug Absorption and Metabolism, Plenum Press: NewYork, NY, 1996; pp 161-192.
233. Ballatori, N. 14.5: Measurement of Hepatobiliary Transport. In:Current Protocols in Toxicology, Supplement 19, John Wiley & Sons, Inc.: 2004; pp 14.15.11-14.15.17.
234. Miller, L. L.; Bly, C. G.; Watson, M. L.; Bale, W. F. The dominantrole of the liver in plasma protein synthesis; a direct study of theisolated perfused rat liver with the aid of lysine-epsilon-C14. J.Exp. Med., 1951, 94(5), 431-453.
235. Miller, L. L. Direct Actions of Insulin, Glucagon, and Epinephrineon the Isolated Perfused Rat Liver. Fed. Proc., 1965, 24, 737-744.
236. Haft, D. E.; Miller, L. L. Enhanced sugar uptake fails to simulatethe insulin effect on lipogenesis in the isolated perfused rat liver.Am. J. Physiol., 1958, 193(3), 469-475.
237. Haft, D. E.; Miller, L. L. Alloxan diabetes and demonstrated directaction of insulin on metabolism of isolated perfused rat liver. Am.J. Physiol., 1958, 192(1), 33-42.
238. Scholz, R.; Bucher, T. Haemoglobin-free perfusion of the rat liver.In: Control of Energy Metabolism, Chance, B., Ed. AcademicPress: New York, NY, 1965; pp 393-414.
239. Prueksaritanont, T.; Hoener, B. A.; Benet, L. Z. Effects of lowdensitylipoprotein and ethinyl estradiol on cyclosporinemetabolism in isolated rat liver perfusions. Drug Metab. Dispos.,1992, 20(4), 547-552.
240. Zamek-Gliszczynsk, i. M. J. a. B., K.L.R. In vitro models forestimating hepatobiliary clearance. In:Pharmaceutical Profiling inDrug Discovery for Lead Selection Borchardt RT, K. E., LipinskiCA, Thakker DR, and Wang B, Ed. American Association ofPharmaceutical Scientists: Arlington, VA, 2004; pp 259-292.
241. Zamek-Gliszczynski, M. J.; Hoffmaster, K. A.; Humphreys, J. E.;Tian, X.; Nezasa, K.; Brouwer, K. L. Differential involvement ofMrp2 (Abcc2) and Bcrp (Abcg2) in biliary excretion of 4- methylumbelliferyl glucuronide and sulfate in the rat. J.Pharmacol. Exp. Ther., 2006, 319(1), 459-467. (Pubitemid 44455153)
242. Vuppugalla, R.; Mehvar, R. Selective effects of nitric oxide on thedisposition of chlorzoxazone and dextromethorphan in isolatedperfused rat livers. Drug Metab. Dispos., 2006, 34(7), 1160-1166.
243. Reichen, J.; Paumgartner, G. Uptake of bile acids by perfused ratliver. Am. J. Physiol., 1976, 231(3), 734-742.
244. Herz, R.; Paumgartner, G.; Preisig, R. Inhibition of bile formationby high doses of taurocholate in the perfused rat liver. Scand. J.Gastroenterol., 1976, 11(7), 741-746.
245. Wu, C. Y.; Benet, L. Z. Disposition of tacrolimus in isolatedperfused rat liver: influence of troleandomycin, cyclosporine, andgg918. Drug Metab. Dispos., 2003, 31(11), 1292-1295. (Pubitemid 37310314)
246. Jeong, H.; Chiou, W. L. Role of P-glycoprotein in the hepaticmetabolism of tacrolimus. Xenobiotica, 2006, 36(1), 1-13.
247. Lau, Y. Y.; Wu, C. Y.; Okochi, H.; Benet, L. Z. Ex situ inhibitionof hepatic uptake and efflux significantly changes metabolism:hepatic enzyme-transporter interplay. J. Pharmacol. Exp. Ther.,2004, 308(3), 1040-1045. (Pubitemid 38263980)
248. Hoffmaster, K. A.; Zamek-Gliszczynski, M. J.; Pollack, G. M.;Brouwer, K. L. Multiple transport systems mediate the hepaticuptake and biliary excretion of the metabolically stable opioidpeptide [D-penicillamine2,5]enkephalin. Drug Metab. Dispos.,2005, 33(2), 287-293. (Pubitemid 40216597)
249. Hoffmaster, K. A.; Zamek-Gliszczynski, M. J.; Pollack, G. M.;Brouwer, K. L. Hepatobiliary disposition of the metabolicallystable opioid peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE):pharmacokinetic consequences of the interplay between multipletransport systems. J. Pharmacol. Exp. Ther,, 2004, 311(3), 1203-1210. (Pubitemid 39612728)
250. Johnson, B. M.; Charman, W. N.; Porter, C. J. H. Application OfCompartmental Modeling To An Examination Of In VitroIntestinal Permeability Data: Assessing The Impact Of TissueUptake, P-Glycoprotein, And Cyp3a. Biopharm. Drug Dispos.,2003, 31(9), 1151-1160. (Pubitemid 37048287)
251. Sevrioukova, I. F.; Poulos, T. L. Structure and mechanism of thecomplex between cytochrome P4503A4 and ritonavir. Proc. Natl.Acad. Sci. U. S. A., 2010, 107(43), 18422-18427.
252. Mahar Doan, K. M.; Humphreys, J. E.; Webster, L. O.; Wring, S.A.; Shampine, L. J.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J.W. Passive permeability and P-glycoprotein-mediated effluxdifferentiate central nervous system (CNS) and non-CNS marketeddrugs. J. Pharmacol. Exp. Ther., 2002, 303(3), 1029-1037. (Pubitemid 35424386)
253. Matsumoto, S.; Yamazoe, Y. Involvement of multiple humancytochromes P450 in the liver microsomal metabolism ofastemizole and a comparison with terfenadine. Br. J. Clin.Pharmacol., 2001, 51(2), 133-142. (Pubitemid 32216061)
254. Wu, X.; Whitfield, L. R.; Stewart, B. H. Atorvastatin transport inthe Caco-2 cell model: contributions of P-glycoprotein and theproton-monocarboxylic acid co-transporter. Pharm. Res., 2000,17(2), 209-215. (Pubitemid 30158371)
255. Park, J. E.; Kim, K. B.; Bae, S. K.; Moon, B. S.; Liu, K. H.; Shin, J.G. Contribution of cytochrome P450 3A4 and 3A5 to themetabolism of atorvastatin. Xenobiotica, 2008, 38(9), 1240-1251.
256. Kim, K. A.; Park, J. Y.; Lee, J. S.; Lim, S. Cytochrome P450 2C8and CYP3A4/5 are involved in chloroquine metabolism in humanliver microsomes. Arch. Pharm. Res., 2003, 26(8), 631-637. (Pubitemid 43080195)
257. Pachot, J. I.; Botham, R. P.; Haegele, K. D.; Hwang, K.Experimental estimation of the role of P-Glycoprotein in thepharmacokinetic behaviour of telithromycin, a novel ketolide, incomparison with roxithromycin and other macrolides using theCaco-2 cell model. J. Pharm. Sci., 2003, 6(1), 1-12. (Pubitemid 37207237)
258. Suzuki, A.; Iida, I.; Hirota, M.; Akimoto, M.; Higuchi, S.; Suwa,T.; Tani, M.; Ishizaki, T.; Chiba, K. CYP isoforms involved in themetabolism of clarithromycin in vitro: comparison between theidentification from disappearance rate and that from formation rateof metabolites. Drug Metab. Pharmacokinet., 2003, 18(2), 104-113.
259. Gertz, M.; Harrison, A.; Houston, J. B.; Galetin, A. Prediction ofhuman intestinal first-pass metabolism of 25 CYP3A substratesfrom in vitro clearance and permeability data. Drug Metab.Dispos., 2010, 38(7), 1147-1158.
260. Dai, Y.; Iwanaga, K.; Lin, Y. S.; Hebert, M. F.; Davis, C. L.;Huang, W.; Kharasch, E. D.; Thummel, K. E. In vitro metabolismof cyclosporine A by human kidney CYP3A5. Biochem.Pharmacol., 2004, 68(9), 1889-1902. (Pubitemid 39278511)
261. Chen, Y.; Agarwal, S.; Shaik, N. M.; Chen, C.; Yang, Z.; Elmquist,W. F. P-glycoprotein and breast cancer resistance protein influencebrain distribution of dasatinib. J. Pharmacol. Exp. Ther., 2009,330(3), 956-963.
262. Wang, L.; Christopher, L. J.; Cui, D.; Li, W.; Iyer, R.; Humphreys,W. G.; Zhang, D. Identification of the human enzymes involved inthe oxidative metabolism of dasatinib: an effective approach fordetermining metabolite formation kinetics. Drug Metab. Dispos.,2008, 36(9), 1828-1839.
263. Ward, B. A.; Morocho, A.; Kandil, A.; Galinsky, R. E.; Flockhart,D. A.; Desta, Z. Characterization of human cytochrome P450enzymes catalyzing domperidone N-dealkylation andhydroxylation in vitro. Br. J. Clin. Pharmacol., 2004, 58(3), 277-287. (Pubitemid 39209061)
264. Wang, R. W.; Newton, D. J.; Scheri, T. D.; Lu, A. Y. Humancytochrome P450 3A4-catalyzed testosterone 6 beta-hydroxylationand erythromycin N-demethylation. Competition during catalysis.Drug Metab. Dispos., 1997, 25(4), 502-507. (Pubitemid 27209375)
265. Kim, W. Y.; Benet, L. Z. P-glycoprotein (P-gp/MDR1)-mediatedefflux of sex-steroid hormones and modulation of P-gp expressionin vitro. Pharm. Res., 2004, 21(7), 1284-1293. (Pubitemid 38954215)
266. Lee, A. J.; Cai, M. X.; Thomas, P. E.; Conney, A. H.; Zhu, B. T.Characterization of the oxidative metabolites of 17beta-estradioland estrone formed by 15 selectively expressed human cytochromep450 isoforms. Endocrinol., 2003, 144(8), 3382-3398. (Pubitemid 36904414)
267. Wang, B.; Sanchez, R. I.; Franklin, R. B.; Evans, D. C.; Huskey, S.E. The involvement of CYP3A4 and CYP2C9 in the metabolism of17 alpha-ethinylestradiol. Drug Metab. Dispos., 2004, 32(11),1209-1212. (Pubitemid 39410903)
268. Troutman, M. D.; Thakker, D. R. Efflux ratio cannot assess Pglycoprotein-mediated attenuation of absorptive transport:asymmetric effect of P-glycoprotein on absorptive and secretorytransport across Caco-2 cell monolayers. Pharm. Res., 2003, 20(8),1200-1209. (Pubitemid 36951845)
269. Zhuo, X.; Zheng, N.; Felix, C. A.; Blair, I. A. Kinetics andregulation of cytochrome P450-mediated etoposide metabolism.Drug Metab. Dispos., 2004, 32(9), 993-1000. (Pubitemid 39096060)
270. Agarwal, S.; Sane, R.; Gallardo, J. L.; Ohlfest, J. R.; Elmquist, W.F. Distribution of gefitinib to the brain is limited by P-glycoprotein(ABCB1) and breast cancer resistance protein (ABCG2)-mediatedactive efflux. J. Pharmacol. Exp. Ther., 2010, 334(1), 147-155.
271. Li, J.; Zhao, M.; He, P.; Hidalgo, M.; Baker, S. D. Differentialmetabolism of gefitinib and erlotinib by human cytochrome P450enzymes. Clin. Cancer Res., 2007, 13(12), 3731-3737. (Pubitemid 46955138)
272. Koudriakova, T.; Iatsimirskaia, E.; Utkin, I.; Gangl, E.; Vouros, P.;Storozhuk, E.; Orza, D.; Marinina, J.; Gerber, N. Metabolism of thehuman immunodeficiency virus protease inhibitors indinavir andritonavir by human intestinal microsomes and expressedcytochrome P4503A4/3A5: mechanism-based inactivation ofcytochrome P4503A by ritonavir. Drug Metab. Dispos., 1998,26(6), 552-561. (Pubitemid 28498361)
273. Kim, K. A.; Chung, J.; Jung, D. H.; Park, J. Y. Identification ofcytochrome P450 isoforms involved in the metabolism ofloperamide in human liver microsomes. Eur. J. Clin. Pharmacol.,2004, 60(8), 575-581. (Pubitemid 39517911)
274. Agarwal, S.; Pal, D.; Mitra, A. K. Both P-gp and MRP2 mediatetransport of Lopinavir, a protease inhibitor. Int. J. Pharm., 2007,339(1-2), 139-147. (Pubitemid 46977600)
275. Kumar, G. N.; Dykstra, J.; Roberts, E. M.; Jayanti, V. K.;Hickman, D.; Uchic, J.; Yao, Y.; Surber, B.; Thomas, S.;Granneman, G. R. Potent inhibition of the cytochrome P-450 3Amediatedhuman liver microsomal metabolism of a novel HIVprotease inhibitor by ritonavir: A positive drug-drug interaction.Drug Metab. Dispos., 1999, 27(8), 902-908. (Pubitemid 29347590)
276. Walker, D. K.; Abel, S.; Comby, P.; Muirhead, G. J.; Nedderman,A. N.; Smith, D. A. Species differences in the disposition of theCCR5 antagonist, UK-427,857, a new potential treatment for HIV.Drug Metab. Dispos., 2005, 33(4), 587-595. (Pubitemid 40393203)
277. Hyland, R.; Dickins, M.; Collins, C.; Jones, H.; Jones, B.Maraviroc: in vitro assessment of drug-drug interaction potential.Br. J. Clin. Pharmacol., 2008, 66(4), 498-507.
278. Crowe, A. The influence of P-glycoprotein on morphine transportin Caco-2 cells. Comparison with paclitaxel. Eur. J. Pharmacol.,2002, 440(1), 7-16. (Pubitemid 34312033)
279. Projean, D.; Morin, P. E.; Tu, T. M.; Ducharme, J. Identification ofCYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes.Xenobiotica, 2003, 33(8), 841-854. (Pubitemid 37129907)
280. Pauli-Magnus, C.; Rekersbrink, S.; Klotz, U.; Fromm, M. F.Interaction of omeprazole, lansoprazole and pantoprazole with Pglycoprotein.Naunyn Schmiedebergs Arch. Pharmacol., 2001,364(6), 551-557. (Pubitemid 33145095)
281. Karam, W. G.; Goldstein, J. A.; Lasker, J. M.; Ghanayem, B. I.Human CYP2C19 is a major omeprazole 5-hydroxylase, asdemonstrated with recombinant cytochrome P450 enzymes. DrugMetab. Dispos., 1996, 24(10), 1081-1087. (Pubitemid 26346220)
282. Chu, X. Y.; Bleasby, K.; Yabut, J.; Cai, X.; Chan, G. H.; Hafey, M.J.; Xu, S.; Bergman, A. J.; Braun, M. P.; Dean, D. C.; Evers, R.Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin byhuman organic anion transporter 3, organic anion transportingpolypeptide 4C1, and multidrug resistance P-glycoprotein. J.Pharmacol. Exp. Ther., 2007, 321(2), 673-683. (Pubitemid 46624514)
283. Ngui, J. S.; Tang, W.; Stearns, R. A.; Shou, M.; Miller, R. R.;Zhang, Y.; Lin, J. H.; Baillie, T. A. Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine. Drug Metab.Dispos., 2000, 28(9), 1043-1050. (Pubitemid 30660358)
284. Iatsimirskaia, E.; Tulebaev, S.; Storozhuk, E.; Utkin, I.; Smith, D.;Gerber, N.; Koudriakova, T. Metabolism of rifabutin in humanenterocyte and liver microsomes: kinetic parameters, identificationof enzyme systems, and drug interactions with macrolides andantifungal agents. Clin. Pharmacol. Ther., 1997, 61(5), 554-562. (Pubitemid 27261759)
285. Alsenz, J.; Steffen, H.; Alex, R. Active apical secretory efflux ofthe HIV protease inhibitors saquinavir and ritonavir in Caco-2 cellmonolayers. Pharm. Res., 1998, 15(3), 423-428. (Pubitemid 28175123)
286. Kumar, G. N.; Rodrigues, A. D.; Buko, A. M.; Denissen, J. F.Cytochrome P450-mediated metabolism of the HIV-1 proteaseinhibitor ritonavir (ABT-538) in human liver microsomes. J.Pharmacol. Exp. Ther., 1996, 277(1), 423-431. (Pubitemid 27169089)
287. Ku, H. Y.; Ahn, H. J.; Seo, K. A.; Kim, H.; Oh, M.; Bae, S. K.;Shin, J. G.; Shon, J. H.; Liu, K. H. The contributions ofcytochromes P450 3A4 and 3A5 to the metabolism of thephosphodiesterase type 5 inhibitors sildenafil, udenafil, andvardenafil. Drug Metab. Dispos., 2008, 36(6), 986-990. (Pubitemid 351717478)
288. Hochman, J. H.; Pudvah, N.; Qiu, J.; Yamazaki, M.; Tang, C.; Lin,J. H.; Prueksaritanont, T. Interactions of human P-glycoproteinwith simvastatin, simvastatin acid, and atorvastatin. Pharm. Res.,2004, 21(9), 1686-1691. (Pubitemid 41184401)
289. Prueksaritanont, T.; Ma, B.; Yu, N. The human hepatic metabolismof simvastatin hydroxy acid is mediated primarily by CYP3A, andnot CYP2D6. Br. J. Clin. Pharmacol., 2003, 56(1), 120-124. (Pubitemid 36886497)
290. Crowe, A.; Lemaire, M. In vitro and in situ absorption of SDZRADusing a human intestinal cell line (Caco-2) and a single passperfusion model in rats: comparison with rapamycin. Pharm. Res.,1998, 15(11), 1666-1672. (Pubitemid 28524574)
291. Picard, N.; Djebli, N.; Sauvage, F. L.; Marquet, P. Metabolism ofsirolimus in the presence or absence of cyclosporine by genotypedhuman liver microsomes and recombinant cytochromes P450 3A4and 3A5. Drug Metab. Dispos., 2007, 35(3), 350-355. (Pubitemid 46333896)
292. Dai, Y.; Hebert, M. F.; Isoherranen, N.; Davis, C. L.; Marsh, C.;Shen, D. D.; Thummel, K. E. Effect of CYP3A5 polymorphism ontacrolimus metabolic clearance in vitro. Drug Metab. Dispos.,2006, 34(5), 836-847.
293. Huang, W.; Lin, Y. S.; McConn, D. J., 2nd; Calamia, J. C.; Totah,R. A.; Isoherranen, N.; Glodowski, M.; Thummel, K. E. Evidenceof significant contribution from CYP3A5 to hepatic drugmetabolism. Drug Metab. Dispos., 2004, 32(12), 1434-1445. (Pubitemid 39564564)
294. Ji, H. Y.; Shim, H. J.; Yoo, M.; Park, E. S.; Lee, H. S. Transport ofa new erectogenic udenafil in Caco-2 cells. Arch. Pharm. Res.,2007, 30(9), 1168-1173.
295. McGinnity, D. F.; Parker, A. J.; Soars, M.; Riley, R. J. Automateddefinition of the enzymology of drug oxidation by the major humandrug metabolizing cytochrome P450s. Drug Metab Dispos, 2000,28(11), 1327-1334.
296. Dennison, J. B.; Kulanthaivel, P.; Barbuch, R. J.; Renbarger, J. L.;Ehlhardt, W. J.; Hall, S. D. Selective metabolism of vincristine invitro by CYP3A5. Drug Metab. Dispos., 2006, 34(8), 1317-1327. (Pubitemid 44079872)