Interplay of transporters and enzymes in drug and metabolite processing

Molecular Pharmaceutics

Volumn 6, Issue 6, 2009, Pages 1734-1755

  Pang, K Sandy ^a   Maeng, Han Joo ^a   Fan, Jianghong ^a   Dan, Leslie L ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

Area under the curve (AUC); Caco 2; Clearance (CL); Enzyme; Excretion; Interplay; Intestine; Liver; Metabolism; Physiologically based pharmacokinetic (PBPK) model; Transporter

Indexed keywords

ABACAVIR; CETIRIZINE; CYCLOSPORIN A; DESLORATADINE; DIGOXIN; DIPHENHYDRAMINE; DOXORUBICIN; ELACRIDAR; ENZYME; ERYTHROMYCIN; GLABRIDIN; GLYCOPROTEIN P; GLYCOPROTEIN P INHIBITOR; GREPAFLOXACIN; HYDROXYZINE; INDINAVIR; LORATADINE; LY 335959; PACLITAXEL; RAPAMYCIN; SALAZOSULFAPYRIDINE; SAQUINAVIR; TACROLIMUS; TANSHINONE; TOPOTECAN; TRAMAZOLINE; TRIPROLIDINE; UNCLASSIFIED DRUG; VINBLASTINE;

AREA UNDER THE CURVE; BASOLATERAL MEMBRANE; DRUG BINDING; DRUG CLEARANCE; DRUG ELIMINATION; DRUG EXCRETION; DRUG INHIBITION; DRUG METABOLISM; HUMAN; KINETICS; LIVER; MEAN RESIDENCE TIME; MONOLAYER CULTURE; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIMULATION; SMALL INTESTINE;

BIOLOGICAL TRANSPORT; CACO-2 CELLS; DRUG INTERACTIONS; ENZYMES; HUMANS; MODELS, BIOLOGICAL; MODELS, THEORETICAL; PHARMACEUTICAL PREPARATIONS;

EID: 71949127231     PISSN: 15438384     EISSN: 15438392     Source Type: Journal    
DOI: 10.1021/mp900258z     Document Type: Review

References (124)

1. Liu, L.; Pang, K. S. The Roles of Transporters and Enzymes in Hepatic Drug Processing. Drug Metab. Dispos. 2005, 33, 1-9.
2. Liu, S.; Tam, D.; Chen, X.; Pang, K. S. P-Glycoprotein and an Unstirred Water Layer Barring Digoxin Absorption in the Vascularly Perfused Rat Small Intestine Preparation: Induction Studies with Pregnenolone-16alpha-Carbonitrile. Drug Metab. Dispos. 2006, 34, 1468-1479.
3. Pang, K. S.; Weiss, M.; Macheras, P. Advanced Pharmacokinetic Models Based on Organ Clearance, Circulatory, and Fractal Concepts. AAPS J. 2007, 9, E268-283.
4. Pang, K. S.; Morris, M. E.; Sun, H. Formed and Preformed Metabolites: Facts and Comparisons. J. Pharm. Pharmacol. 2008, 60, 1247-1275.
5. Eloranta, J. J.; Kullak-Ublick, G. A. Coordinate Transcriptional Regulation of Bile Acid Homeostasis and Drug Metabolism. Arch. Biochem. Biophys. 2005, 433, 397-412. (Pubitemid 39592794)
6. Shitara, Y.; Horie, T.; Sugiyama, Y. Transporters as a Determinant of Drug Clearance and Tissue Distribution. Eur. J. Pharm. Sci. 2006, 27, 425-446. (Pubitemid 43363338)
7. Russel, F. G.; Koenderink, J. B.; Masereeuw, R. Multidrug Resistance Protein 4 (Mrp4/Abcc4): A Versatile Efflux Transporter for Drugs and Signalling Molecules. Trends Pharmacol. Sci. 2008, 29, 200-207.
8. Moriyama, Y.; Hiasa, M.; Matsumoto, T.; Omote, H. Multidrug and Toxic Compound Extrusion (MATE)-Type Proteins as Anchor Transporters for the Excretion of Metabolic Waste Products and Xenobiotics. Xenobiotica 2008, 38, 1107-1118.
9. Trauner, M.; Boyer, J. L. Bile Salt Transporters: Molecular Characterization, Function, and Regulation. Physiol. Rev. 2003, 83, 633-671. (Pubitemid 36378680)
10. van Montfoort, J. E.; Hagenbuch, B.; Groothuis, G. M.; Koepsell, H.; Meier, P. J.; Meijer, D. K. Drug Uptake Systems in Liver and Kidney. Curr. Drug Metab. 2003, 4, 185-211.
11. Robey, R. W.; Polgar, O.; Deeken, J.; To, K. W.; Bates, S. E. Abcg2: Determining Its Relevance in Clinical Drug Resistance. Cancer Metastasis Rev. 2007, 26, 39-57.
12. Nies, A. T.; Schwab, M.; Keppler, D. Interplay of Conjugating Enzymes with Oatp Uptake Transporters and Abcc/Mrp Efflux Pumps in the Elimination of Drugs. Expert Opin. Drug Metab. Toxicol. 2008, 4, 545-568. (Pubitemid 351890738)
13. Borst, P.; de Wolf, C.; van de Wetering, K. Multidrug Resistance-Associated Proteins 3, 4, and 5. Pfluegers Arch. 2007, 453, 661-673.
14. Rius, M.; Nies, A. T.; Hummel-Eisenbeiss, J.; Jedlitschky, G.; Keppler, D. Cotransport of Reduced Glutathione with Bile Salts by Mrp4 (Abcc4) Localized to the Basolateral Hepatocyte Membrane. Hepatology 2003, 38, 374-384. (Pubitemid 36919858)
15. van Aubel, R. A.; Smeets, P. H.; Peters, J. G.; Bindels, R. J.; Russel, F. G. The Mrp4/Abcc4 Gene Encodes a Novel Apical Organic Anion Transporter in Human Kidney Proximal Tubules: Putative Efflux Pump for Urinary cAMP and cGMP. J. Am. Soc. Nephrol. 2002, 13, 595-603.
16. Li, C.; Krishnamurthy, P. C.; Penmatsa, H.; Marrs, K. L.; Wang, X. Q.; Zaccolo, M.; Jalink, K.; Li, M.; Nelson, D. J.; Schuetz, J. D.; Naren, A. P. Spatiotemporal Coupling of cAMP Transporter to CFTR Chloride Channel Function in the Gut Epithelia. Cell 2007, 131, 940-951.
17. Belinsky, M. G.; Dawson, P. A.; Shchaveleva, I.; Bain, L. J.; Wang, R.; Ling, V.; Chen, Z. S.; Grinberg, A.; Westphal, H.; Klein-Szanto, A.; Lerro, A.; Kruh, G. D. Analysis of the in Vivo Functions of Mrp3. Mol. Pharmacol. 2005, 68, 160-168.
18. Stieger, B.; Meier, Y.; Meier, P. J. The Bile Salt Export Pump. Pfluegers Arch. 2007, 453, 611-620.
19. Wacher, V. J.; Silverman, J. A.; Zhang, Y.; Benet, L. Z. Role of P-Glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics. J. Pharm. Sci. 1998, 87, 1322-1330. (Pubitemid 28514135)
20. Schuetz, E. G.; Schinkel, A. H. Drug Disposition as Determined by the Interplay between Drug-Transporting and Drug-Metabolizing Systems. J. Biochem. Mol. Toxicol. 1999, 13, 219-222.
21. Tachibana, T.; Kato, M.; Watanabe, T.; Mitsui, T.; Sugiyama, Y. Method for Predicting the Risk of Drug-Drug Interactions Involving Inhibition of Intestinal Cyp3A4 and P-Glycoprotein. Xenobiotica 2009, 39, 430-443.
22. Schinkel, A. H.; Mayer, U.; Wagenaar, E.; Mol, C. A.; van Deemter, 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 Lacking Mdr1-Type (Drug-Transporting) P-Glycoproteins. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 4028-4033.
23. Jansen, P. L.; Peters, W. H.; Meijer, D. K. Hepatobiliary Excretion of Organic Anions in Double-Mutant Rats with a Combination of Defective Canalicular Transport and Uridine 5′-Diphosphate-Glucuronyltransferase Deficiency. Gastroenterology 1987, 93, 1094-1103.
24. Yamazaki, K.; Mikami, T.; Hosokawa, S.; Tagaya, O.; Nozaki, Y.; Kawaguchi, A.; Funami, H.; Katoh, H.; Yamamoto, N.; Wakabayashi, T. A New Mutant Rat with Hyperbilirubinuria (Hyb). J. Hered. 1995, 86, 314-317.
25. Ito, K.; Suzuki, H.; Hirohashi, T.; Kume, K.; Shimizu, T.; Sugiyama, Y. Molecular Cloning of Canalicular Multispecific Organic Anion Transporter Defective in EHBR. Am. J. Physiol. 1997, 272, G16-22. (Pubitemid 127749985)
26. Chen, C.; Liu, X.; Smith, B. J. Utility of Mdr1-Gene Deficient Mice in Assessing the Impact of P-Glycoprotein on Pharmacokinetics and Pharmacodynamics in Drug Discovery and Development. Curr. Drug Metab. 2003, 4, 272-291.
27. Kim, R. B.; Wandel, C.; Leake, B.; Cvetkovic, M.; Fromm, M. F.; Dempsey, P. J.; Roden, M. M.; Belas, F.; Chaudhary, A. K.; Roden, D. M.; Wood, A. J.; Wilkinson, G. R. Interrelationship between Substrates and Inhibitors of Human Cyp3A and P-Glycoprotein. Pharm. Res. 1999, 16, 408-414.
28. Gillette, J. R. Factors Affecting Drug Metabolism. Ann. N.Y. Acad. Sci. 1971, 179, 43-66.
29. Wilkinson, G. R.; Shand, D. G. Commentary: A Physiological Approach to Hepatic Drug Clearance. Clin. Pharmacol. Ther. 1975, 18, 377-390.
30. Sirianni, G. L.; Pang, K. S. Organ Clearance Concepts: New Perspectives on Old Principles. J. Pharmacokinet. Biopharm. 1997, 25, 449-470.
31. Sun, H.; Pang, K. S. Disparity in Intestine Disposition between Formed and Preformed Metabolites and Implications: A Theoretical Study. Drug Metab. Dispos. 2009, 37, 187-202.
32. Sun, H.; Pang, K. S. Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study. Drug Metab. Dispos. 2008, 36, 102-123.
33. Cummins, C. L.; Mangravite, L. M.; Benet, L. Z. Characterizing the Expression of Cyp3A4 and Efflux Transporters (P-gp, Mrp1, and Mrp2) in Cyp3A4-Transfected Caco-2 Cells after Induction with Sodium Butyrate and the Phorbol Ester 12-O-Tetradecanoylphorbol-13-Acetate. Pharm. Res. 2001, 18, 1102-1109.
34. Schmiedlin-Ren, P.; Thummel, K. E.; Fisher, J. M.; Paine, M. F.; Watkins, P. B. Induction of Cyp3A4 by 1 α,25-Dihydroxyvitamin D3 Is Human Cell Line-Specific and Is Unlikely to Involve Pregnane X Receptor. Drug Metab. Dispos. 2001, 29, 1446-1453.
35. Gan, L. S.; Moseley, M. A.; Khosla, B.; Augustijns, P. F.; Bradshaw, T. P.; Hendren, R. W.; Thakker, D. R. Cyp3A-Like Cytochrome P450-Mediated Metabolism and Polarized Efflux of Cyclosporin A in Caco-2 Cells. Drug Metab. Dispos. 1996, 24, 344-349.
36. 3-Modified Caco-2 Cell Monolayers. J. Pharmacol. Exp. Ther. 1999, 289, 1134-1142.
37. Hochman, J. H.; Chiba, M.; Nishime, J.; Yamazaki, M.; Lin, J. H. Influence of P-Glycoprotein on the Transport and Metabolism of Indinavir in Caco-2 Cells Expressing Cytochrome P-450 3A4. J. Pharmacol. Exp. Ther. 2000, 292, 310-318.
38. Cummins, C. L.; Jacobsen, W.; Benet, L. Z. Unmasking the Dynamic Interplay between Intestinal P-Glycoprotein and Cyp3A4. J. Pharmacol. Exp. Ther. 2002, 300, 1036-1045.
39. Cummins, C. L.; Jacobsen, W.; Christians, U.; Benet, L. Z. Cyp3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and Midazolam. J. Pharmacol. Exp. Ther. 2004, 308, 143-155.
40. Benet, L. Z.; Cummins, C. L.; Wu, C. Y. Unmasking the Dynamic Interplay between Efflux Transporters and Metabolic Enzymes. Int. J. Pharm. 2004, 277, 3-9.
41. Chan, L. M.; Cooper, A. E.; Dudley, A. L.; Ford, D.; Hirst, B. H. P-Glycoprotein Potentiates Cyp3A4-Mediated Drug Disappearance During Caco-2 Intestinal Secretory Detoxification. J. Drug Targeting 2004, 12, 405-413.
42. Christians, U.; Schmitz, V.; Haschke, M. Functional Interactions between P-Glycoprotein and Cyp3A in Drug Metabolism. Expert Opin. Drug Metab. Toxicol. 2005, 1, 641-654.
43. Mouly, S. J.; Paine, M. F.; Watkins, P. B. Contributions of Cyp3A4, P-Glycoprotein, and Serum Protein Binding to the Intestinal First-Pass Extraction of Saquinavir. J. Pharmacol. Exp. Ther. 2004, 308, 941-948.
44. Tam, D.; Sun, H.; Pang, K. S. Influence of P-Glycoprotein, Transfer Clearances, and Drug Binding on Intestinal Metabolism in Caco-2 Cell Monolayers or Membrane Preparations: A Theoretical Analysis. Drug Metab. Dispos. 2003, 31, 1214-1226.
45. Sun, H.; Chow, E. C.; Liu, S.; Du, Y.; Pang, K. S. The Caco-2 Cell Monolayer: Usefulness and Limitations. Expert Opin. Drug Metab. Toxicol. 2008, 4, 395-411.
46. Fan, J.; Maeng, H. J.; Pang, K. S. Interplay of Transporters and Enzymes in the Caco-2 Cell Monolayer. I. Effect of Altered Apical Secretion. Submitted.
47. Knight, B.; Troutman, M.; Thakker, D. R. Deconvoluting the Effects of P-Glycoprotein on Intestinal Cyp3A: A Major Challenge. Curr. Opin. Pharmacol. 2006, 6, 528-532.
48. Eagling, V. A.; Wiltshire, H.; Whitcombe, I. W.; Back, D. J. Cyp3A4-Mediated Hepatic Metabolism of the HIV-1 Protease Inhibitor Saquinavir in Vitro. Xenobiotica 2002, 32, 1-17. (Pubitemid 34095130)
49. Fitzsimmons, M. E.; Collins, J. M. Selective Biotransformation of the Human Immunodeficiency Virus Protease Inhibitor Saquinavir by Human Small-Intestinal Cytochrome P4503A4: Potential Contribution to High First-Pass Metabolism. Drug Metab. Dispos. 1997, 25, 256-266.
50. Foger, F.; Kafedjiiski, K.; Hoyer, H.; Loretz, B.; Bernkop-Schnurch, A. Enhanced Transport of P-Glycoprotein Substrate Saquinavir in Presence of Thiolated Chitosan. J. Drug. Targeting 2007, 15, 132-139. (Pubitemid 46957699)
51. Usansky, H. H.; Hu, P.; Sinko, P. J. Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and Cyp3A on Saquinavir Oral Absorption in Sprague-Dawley Rats. Drug Metab. Dispos. 2008, 36, 863-869.
52. Balani, S. K.; Woolf, E. J.; Hoagland, V. L.; Sturgill, M. G.; Deutsch, P. J.; Yeh, K. C.; Lin, J. H. Disposition of Indinavir, a Potent HIV-1 Protease Inhibitor, after an Oral Dose in Humans. Drug Metab. Dispos. 1996, 24, 1389-1394.
53. Chiba, M.; Hensleigh, M.; Nishime, J. A.; Balani, S. K.; Lin, J. H. Role of Cytochrome P450 3A4 in Human Metabolism of MK-639, a Potent Human Immunodeficiency Virus Protease Inhibitor. Drug Metab. Dispos. 1996, 24, 307-314. (Pubitemid 26087084)
54. Kim, R. B.; Fromm, M. F.; Wandel, C.; Leake, B.; Wood, A. J.; Roden, D. M.; Wilkinson, G. R. The Drug Transporter P-Glycoprotein Limits Oral Absorption and Brain Entry of HIV-1 Protease Inhibitors. J. Clin. Invest. 1998, 101, 289-294.
55. Lee, C. G.; Gottesman, M. M.; Cardarelli, C. O.; Ramachandra, M.; Jeang, K. T.; Ambudkar, S. V.; Pastan, I.; Dey, S. HIV-1 Protease Inhibitors Are Substrates for the Mdr1 Multidrug Transporter. Biochemistry 1998, 37, 3594-3601. (Pubitemid 28162914)
56. Johnson, B. M.; Charman, W. N.; Porter, C. J. H. The Impact of P-Glycoprotein Efflux on Enterocyte Residence Time and Enterocyte-Based Metabolism of Verapamil. J. Pharm. Pharmacol. 2001, 53, 1611-1619.
57. Johnson, B. M.; Chen, W.; Borchardt, R. T.; Charman, W. N.; Porter, C. J. H. A Kinetic Evaluation of the Absorption, Efflux, and Metabolism of Verapamil in the Autoperfused Rat Jejunum. J. Pharmacol. Exp. Ther. 2003, 305, 151-158.
58. Johnson, B. M.; Charman, W. N.; Porter, C. J. Application of Compartmental Modeling to an Examination of in Vitro Intestinal Permeability Data: Assessing the Impact of Tissue Uptake, P-Glycoprotein, and Cyp3A. Drug Metab. Dispos. 2003, 31, 1151-1160.
59. Pal, D.; Mitra, A. K. Mdr- and Cyp3A4-Mediated Drug-Drug Interactions. J. Neuroimmune Pharmacol. 2006, 1, 323-339.
60. Morris, M. E.; Pang, K. S. Competition between Two Enzymes for Substrate Removal in Liver: Modulating Effects Due to Substrate Recruitment of Hepatocyte Activity. J. Pharmacokinet. Biopharm. 1987, 15, 473-496.
61. Liu, L.; Pang, K. S. An Integrated Approach to Model Hepatic Drug Clearance. Eur. J. Pharm. Sci. 2006, 29, 215-230. (Pubitemid 44602411)
62. Sekine, S.; Ito, K.; Horie, T. Oxidative Stress and Mrp2 Internalization. Free Radical Biol. Med. 2006, 40, 2166-2174.
63. Perez, L. M.; Milkiewicz, P.; Elias, E.; Coleman, R.; Sanchez Pozzi, E. J.; Roma, M. G. Oxidative Stress Induces Internalization of the Bile Salt Export Pump, Bsep, and Bile Salt Secretory Failure in Isolated Rat Hepatocyte Couplets: A Role for Protein Kinase C and Prevention by Protein Kinase A. Toxicol. Sci. 2006, 91, 150-158.
64. Bow, D. A.; Perry, J. L.; Miller, D. S.; Pritchard, J. B.; Brouwer, K. L. Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in Freshly Isolated Rat Hepatocytes. Drug Metab. Dispos. 2008, 36, 198-202.
65. Sun, H.; Liu, L.; Pang, K. S. Increased Estrogen Sulfation of Estradiol 17β-D-Glucuronide in Metastatic Tumor Rat Livers. J. Pharmacol. Exp. Ther. 2006, 319, 818-831.
66. Sun, H.; Zeng, Y.; Pang, K. S. Interplay of Phase II Transporters and Enzymes in Futile Cycling: Influence of Estradiol 17β D-glucuronide and Estradiol 3-sulfate-17β-D glucuronide Excretion by Mrp2 on Net Sulfation in TR- and Wistar Perfused Rat Liver Preparations. Drug Metab. Dispos., under revision.
67. van Asperen, J.; Schinkel, A. H.; Beijnen, J. H.; Nooijen, W. J.; Borst, P.; van Tellingen, O. Altered Pharmacokinetics of Vinblastine in Mdr1a P-Glycoprotein-Deficient Mice. J. Natl. Cancer Inst. 1996, 88, 994-999.
68. Sparreboom, A.; van Asperen, J.; Mayer, U.; Schinkel, A. H.; Smit, J. W.; Meijer, D. K.; Borst, P.; Nooijen, W. J.; Beijnen, J. H.; van Tellingen, O. Limited Oral Bioavailability and Active Epithelial Excretion of Paclitaxel (Taxol) Caused by P-Glycoprotein in the Intestine. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2031-2035.
69. Yokogawa, K.; Takahashi, M.; Tamai, I.; Konishi, H.; Nomura, M.; Moritani, S.; Miyamoto, K.; Tsuji, A. P-Glycoprotein-Dependent Disposition Kinetics of Tacrolimus: Studies in Mdr1a Knockout Mice. Pharm. Res. 1999, 16, 1213-1218. (Pubitemid 29393609)
70. Kawahara, M.; Sakata, A.; Miyashita, T.; Tamai, I.; Tsuji, A. Physiologically Based Pharmacokinetics of Digoxin in Mdr1a Knockout Mice. J. Pharm. Sci. 1999, 88, 1281-1287.
71. Kwei, G. Y.; Alvaro, R. F.; Chen, Q.; Jenkins, H. J.; Hop, C. E.; Keohane, C. A.; Ly, V. T.; Strauss, J. R.; Wang, R. W.; Wang, Z.; Pippert, T. R.; Umbenhauer, D. R. Disposition of Ivermectin and Cyclosporin A in CF-1 Mice Deficient in Mdr1a P-Glycoprotein. Drug Metab. Dispos. 1999, 27, 581-587.
72. van Asperen, J.; van Tellingen, O.; Tijssen, F.; Schinkel, A. H.; Beijnen, J. H. Increased Accumulation of Doxorubicin and Doxorubicinol in Cardiac Tissue of Mice Lacking Mdr1a P-Glycoprotein. Br. J. Cancer 1999, 79, 108-113.
73. Bardelmeijer, H. A.; Beijnen, J. H.; Brouwer, K. R.; Rosing, H.; Nooijen, W. J.; Schellens, J. H.; van Tellingen, O. Increased Oral Bioavailability of Paclitaxel by GF120918 in Mice through Selective Modulation of P-Glycoprotein. Clin. Cancer Res. 2000, 6, 4416-4421.
74. Shaik, N.; Giri, N.; Pan, G.; Elmquist, W. F. P-Glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain Distribution. Drug Metab. Dispos. 2007, 35, 2076-2085.
75. Chen, C.; Hanson, E.; Watson, J. W.; Lee, J. S. P-Glycoprotein Limits the Brain Penetration of Nonsedating but Not Sedating H1-Antagonists. Drug Metab. Dispos. 2003, 31, 312-318.
76. Lan, L. B.; Dalton, J. T.; Schuetz, E. G. Mdr1 Limits Cyp3A Metabolism in Vivo. Mol. Pharmacol. 2000, 58, 863-869.
77. Cao, J.; Chen, X.; Liang, J.; Yu, X. Q.; Xu, A. L.; Chan, E.; Wei, D.; Huang, M.; Wen, J. Y.; Yu, X. Y.; Li, X. T.; Sheu, F. S.; Zhou, S. F. Role of P-Glycoprotein in the Intestinal Absorption of Glabridin, an Active Flavonoid from the Root of Glycyrrhiza Glabra. Drug Metab. Dispos. 2007, 35, 539-553. (Pubitemid 46513256)
78. Yu, X. Y.; Lin, S. G.; Zhou, Z. W.; Chen, X.; Liang, J.; Liu, P. Q.; Duan, W.; Chowbay, B.; Wen, J. Y.; Li, C. G.; Zhou, S. F. Role of P-Glycoprotein in the Intestinal Absorption of Tanshinone Iia, a Major Active Ingredient in the Root of Salvia Miltiorrhiza Bunge. Curr. Drug Metab. 2007, 8, 325-340. (Pubitemid 46780062)
79. Prueksaritanont, T.; Meng, Y.; Ma, B.; Leppert, P.; Hochman, J.; Tang, C.; Perkins, J.; Zrada, M.; Meissner, R.; Duggan, M. E.; Lin, J. H. Differences in the Absorption, Metabolism and Biliary Excretion of a Diastereomeric Pair of Alphavbeta3-Antagonists in Rat: Limited Role of P-Glycoprotein. Xenobiotica 2002, 32, 207-220.
80. Sasabe, H.; Kato, Y.; Suzuki, T.; Itose, M.; Miyamoto, G.; Sugiyama, Y. Differential Involvement of Multidrug Resistance-Associated Protein 1 and P-Glycoprotein in Tissue Distribution and Excretion of Grepafloxacin in Mice. J. Pharmacol. Exp. Ther. 2004, 310, 648-655. (Pubitemid 38988910)
81. Jin, M.; Shimada, T.; Yokogawa, K.; Nomura, M.; Ishizaki, J.; Piao, Y.; Kato, Y.; Tsuji, A.; Miyamoto, K. Site-Dependent Contributions of P-Glycoprotein and Cyp3A to Cyclosporin A Absorption, and Effect of Dexamethasone in Small Intestine of Mice. Biochem. Pharmacol. 2006, 72, 1042-1050. (Pubitemid 44374466)
82. de Vries, N. A.; Zhao, J.; Kroon, E.; Buckle, T.; Beijnen, J. H.; van Tellingen, O. P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan. Clin. Cancer Res. 2007, 13, 6440-6449.
83. Zaher, H.; Khan, A. A.; Palandra, J.; Brayman, T. G.; Yu, L.; Ware, J. A. Breast Cancer Resistance Protein (Bcrp/Abcg2) Is a Major Determinant of Sulfasalazine Absorption and Elimination in the Mouse. Mol. Pharmaceutics 2006, 3, 55-61.
84. Chiou, W. L.; Chung, S. M.; Wu, T. C. Potential Role of P-Glycoprotein in Affecting Hepatic Metabolism of Drugs. Pharm. Res. 2000, 17, 903-905. (Pubitemid 30736589)
85. Jeong, H.; Chiou, W. L. Role of P-Glycoprotein in the Hepatic Metabolism of Tacrolimus. Xenobiotica 2006, 36, 1-13.
86. Lam, J. L.; Benet, L. Z. Hepatic Microsome Studies Are Insufficient to Characterize in Vivo Hepatic Metabolic Clearance and Metabolic Drug-Drug Interactions: Studies of Digoxin Metabolism in Primary Rat Hepatocytes Versus Microsomes. Drug Metab. Dispos. 2004, 32, 1311-1316.
87. Lam, J. L.; Okochi, H.; Huang, Y.; Benet, L. Z. In Vitro and in Vivo Correlation of Hepatic Transporter Effects on Erythromycin Metabolism: Characterizing the Importance of Transporter-Enzyme Interplay. Drug Metab. Dispos. 2006, 34, 1336-1344.
88. Wu, C. Y.; Benet, L. Z. Disposition of Tacrolimus in Isolated Perfused Rat Liver: Influence of Troleandomycin, Cyclosporine, and GG918. Drug Metab. Dispos. 2003, 31, 1292-1295.
89. Lau, Y. Y.; Wu, C. Y.; Okochi, H.; Benet, L. Z. Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay. J. Pharmacol. Exp. Ther. 2004, 308, 1040-1045.
90. Lau, Y. Y.; Okochi, H.; Huang, Y.; Benet, L. Z. Pharmacokinetics of Atorvastatin and Its Hydroxy Metabolites in Rats and the Effects of Concomitant Rifampicin Single Doses: Relevance of First-Pass Effect From Hepatic Uptake Transporters, and Intestinal and Hepatic Metabolism. Drug Metab. Dispos. 2006, 34, 1175-1181.
91. Lau, Y. Y.; Okochi, H.; Huang, Y.; Benet, L. Z. Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and Ex Situ Systems. J. Pharmacol. Exp. Ther. 2006, 316, 762-771. (Pubitemid 43131004)
92. Funakoshi, S.; Murakami, T.; Yumoto, R.; Kiribayashi, Y.; Takano, M. Role of Organic Anion Transporting Polypeptide 2 in Pharmacokinetics of Digoxin and Beta-Methyldigoxin in Rats. J. Pharm. Sci. 2005, 94, 1196-1203. (Pubitemid 40904184)
93. Kurnik, D.; Wood, A. J.; Wilkinson, G. R. The Erythromycin Breath Test Reflects P-Glycoprotein Function Independently of Cytochrome P450 3A Activity. Clin. Pharmacol. Ther. 2006, 80, 228-234.
94. Lau, Y. Y.; Huang, Y.; Frassetto, L.; Benet, L. Z. Effect of OATP1B Transporter Inhibition on the Pharmacokinetics of Atorvastatin in Healthy Volunteers. Clin. Pharmacol. Ther. 2007, 81, 194-204. (Pubitemid 46174816)
95. Hermann, M.; Asberg, A.; Christensen, H.; Holdaas, H.; Hartmann, A.; Reubsaet, J. L. Substantially Elevated Levels of Atorvastatin and Metabolites in Cyclosporine-Treated Renal Transplant Recipients. Clin. Pharmacol. Ther. 2004, 76, 388-391.
96. Suzuki, H.; Sugiyama, Y. Role of Metabolic Enzymes and Efflux Transporters in the Absorption of Drugs from the Small Intestine. Eur. J. Pharm. Sci. 2000, 12, 3-12. (Pubitemid 30838440)
97. Wacher, V. J.; Salphati, L.; Benet, L. Z. Active Secretion and Enterocytic Drug Metabolism Barriers to Drug Absorption. Adv. Drug Delivery Rev. 2001, 46, 89-102.
98. Pang, K. S. Modeling of Intestinal Drug Absorption: Roles of Transporters and Metabolic Enzymes (for the Gillette Review Series). Drug Metab. Dispos. 2003, 31, 1507-1519.
99. Kivisto, K. T.; Niemi, M.; Fromm, M. F. Functional Interaction of Intestinal Cyp3A4 and P-Glycoprotein. Fundam. Clin. Pharmacol. 2004, 18, 621-626.
100. von Richter, O.; Burk, O.; Fromm, M. F.; Thon, K. P.; Eichelbaum, M.; Kivisto, K. T. Cytochrome P450 3A4 and P-Glycoprotein Expression in Human Small Intestinal Enterocytes and Hepatocytes: A Comparative Analysis in Paired Tissue Specimens. Clin Pharmacol. Ther. 2004, 75, 172-183.
101. Christians, U. Transport Proteins and Intestinal Metabolism: P-Glycoprotein and Cytochrome P4503A. Ther. Drug Monit. 2004, 26, 104-106.
102. Cong, D.; Doherty, M.; Pang, K. S. A New Physiologically Based, Segregated-Flow Model to Explain Route-Dependent Intestinal Metabolism. Drug Metab. Dispos. 2000, 28, 224-235.
103. Ito, K.; Kusuhara, H.; Sugiyama, Y. Effects of Intestinal Cyp3A4 and P-Glycoprotein on Oral Drug Absorption - Theoretical Approach. Pharm. Res. 1999, 16, 225-231. (Pubitemid 29135126)
104. Doherty, M. M.; Pang, K. S. Route-Dependent Metabolism of Morphine in the Vascularly Perfused Rat Small Intestine Preparation. Pharm. Res. 2000, 17, 291-298.
105. Yang, J.; Jamei, M.; Yeo, K. R.; Rostami-Hodjegan, A. Prediction of intestinal first-pass drug metabolism. Curr. Drug Metab. 2007, 8 (7), 676-684. (Pubitemid 47578116)
106. Lin, J. H.; Chiba, M.; Baillie, T. A. Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized. Pharmacol. Rev. 1999, 51, 135-158.
107. Yu, L. X.; Amidon, G. L. Saturable Small Intestinal Drug Absorption in Humans: Modeling and Interpretation of Cefatrizine Data. Eur. J. Pharm. Biopharm. 1998, 45, 199-203.
108. Yu, L. X.; Amidon, G. L. A Compartmental Absorption and Transit Model for Estimating Oral Drug Absorption. Int. J. Pharm. 1999, 186, 119-125. (Pubitemid 29459038)
109. Shono, Y.; Jantratid, E.; Janssen, N.; Kesisoglou, F.; Mao, Y.; Vertzoni, M.; Reppas, C.; Dressman, J. B. Prediction of Food Effects on the Absorption of Celecoxib Based on Biorelevant Dissolution Testing Coupled with Physiologically Based Pharmacokinetic Modeling. Eur. J. Pharm. Biopharm. 2009, 73, 107-114.
110. Willmann, S.; Edginton, A. N.; Dressman, J. B. Development and Validation of a Physiology-Based Model for the Prediction of Oral Absorption in Monkeys. Pharm. Res. 2007, 24, 1275-1282.
111. Willmann, S.; Schmitt, W.; Keldenich, J.; Dressman, J. B. A Physiologic Model for Simulating Gastrointestinal Flow and Drug Absorption in Rats. Pharm. Res. 2003, 20, 1766-1771.
112. Tam, D.; Tirona, R. G.; Pang, K. S. Segmental Intestinal Transporters and Metabolic Enzymes on Intestinal Drug Absorption. Drug Metab. Dispos. 2003, 31, 373-383. (Pubitemid 36378514)
113. Paine, M. F.; Khalighi, M.; Fisher, J. M.; Shen, D. D.; Kunze, K. L.; Marsh, C. L.; Perkins, J. D.; Thummel, K. E. Characterization of Interintestinal and Intraintestinal Variations in Human Cyp3A-Dependent Metabolism. J. Pharmacol. Exp. Ther. 1997, 283, 1552-1562.
114. Taipalensuu, J.; Tornblom, H.; Lindberg, G.; Einarsson, C.; Sjoqvist, F.; Melhus, H.; Garberg, P.; Sjostrom, B.; Lundgren, B.; Artursson, P. Correlation of Gene Expression of Ten Drug Efflux Proteins of the ATP-Binding Cassette Transporter Family in Normal Human Jejunum and in Human Intestinal Epithelial Caco-2 Cell Monolayers. J. Pharmacol. Exp. Ther. 2001, 299, 164-170. (Pubitemid 32905131)
115. Mouly, S.; Paine, M. F. P-Glycoprotein Increases from Proximal to Distal Regions of Human Small Intestine. Pharm. Res. 2003, 20, 1595-1599.
116. Mutch, D. M.; Anderle, P.; Fiaux, M.; Mansourian, R.; Vidal, K.; Wahli, W.; Williamson, G.; Roberts, M. A. Regional Variations in ABC Transporter Expression Along the Mouse Intestinal Tract. Physiol. Genomics 2004, 17, 11-20.
117. Englund, G.; Rorsman, F.; Ronnblom, A.; Karlbom, U.; Lazorova, L.; Grasjo, J.; Kindmark, A.; Artursson, P. Regional Levels of Drug Transporters Along the Human Intestinal Tract: Co-Expression of ABC and SLC Transporters and Comparison with Caco-2 Cells. Eur. J. Pharm. Sci. 2006, 29, 269-277. (Pubitemid 44602404)
118. Chen, X.; Chen, F.; Liu, S.; Glaeser, H.; Dawson, P. A.; Hofmann, A. F.; Kim, R. B.; Shneider, B. L.; Pang, K. S. Transactivation of Rat Apical Sodium-Dependent Bile Acid Transporter and Increased Bile Acid Transport by 1R,25-Dihydroxyvitamin D3 Via the Vitamin D Receptor. Mol. Pharmacol. 2006, 69, 1913-1923.
119. Meier, Y.; Eloranta, J. J.; Darimont, J.; Ismair, M. G.; Hiller, C.; Fried, M.; Kullak-Ublick, G. A.; Vavricka, S. R. Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract. Drug Metab. Dispos. 2007, 35, 590-594.
120. Mitschke, D.; Reichel, A.; Fricker, G.; Moenning, U. Characterization of Cytochrome P450 Protein Expression Along the Entire Length of the Intestine of Male and Female Rats. Drug Metab. Dispos. 2008, 36, 1039-1045. (Pubitemid 351717460)
121. 3 Triggered Vitamin D Receptor and Farnesoid X Receptor-Like Effects in Rat Intestine and Liver in Vivo. Biopharm. Drug Dispos. 2009, 30, 457-475.
122. Badhan, R.; Penny, J.; Galetin, A.; Houston, J. B. Methodology for Development of a Physiological Model Incorporating Cyp3A and P-Glycoprotein for the Prediction of Intestinal Drug Absorption. J. Pharm. Sci. 2009, 98, 2180-2197.
123. Usansky, H. H.; Hu, P.; Sinko, P. J. Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and Cyp3A on Saquinavir Oral Absorption in Sprague-Dawley Rats. Drug Metab. Dispos. 2008, 36, 863-869.
124. Cummins, C. L.; Salphati, L.; Reid, M. J.; Benet, L. Z. In Vivo Modulation of Intestinal Cyp3A Metabolism by P-Glycoprotein: Studies Using the Rat Single-Pass Intestinal Perfusion Model. J. Pharmacol. Exp. Ther. 2003, 305, 306-314.