Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models

Clinical Pharmacokinetics

Volumn 55, Issue 6, 2016, Pages 673-696

  Peters, Sheila Annie ^a   Jones, Christopher R ^b   Ungell, Anna Lena ^c   Hatley, Oliver J D ^d  

^a MERCK KGAA   (Germany)

^b ASTRAZENECA   (United Kingdom)

^c UCB PHARMA   (Belgium)

^d CERTARA UK LIMITED   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CARRIER PROTEIN; CYTOCHROME P450 3A; DRUG METABOLIZING ENZYME; ABC TRANSPORTER; GLUCURONOSYLTRANSFERASE; SULFOTRANSFERASE;

DRUG BIOAVAILABILITY; ENZYME SPECIFICITY; HUMAN; IN VIVO STUDY; INTESTINE WALL; KNOCKOUT MOUSE; MATHEMATICAL MODEL; METABOLISM; NONHUMAN; PREDICTIVE VALUE; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVIEW; TRANSGENIC MOUSE; ANIMAL; ANIMAL MODEL; AREA UNDER THE CURVE; BIOLOGICAL MODEL; DRUG INTERACTION; ENZYMOLOGY; FOOD DRUG INTERACTION; INTESTINE ABSORPTION; INTESTINE CELL; INTESTINE MUCOSA; METABOLIC CLEARANCE RATE; PH; PHARMACOKINETICS; PHYSIOLOGY; TRANSGENIC ANIMAL;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; AREA UNDER CURVE; ATP-BINDING CASSETTE TRANSPORTERS; CYTOCHROME P-450 CYP3A; DRUG INTERACTIONS; ENTEROCYTES; FOOD-DRUG INTERACTIONS; GLUCURONOSYLTRANSFERASE; HUMANS; HYDROGEN-ION CONCENTRATION; INTESTINAL ABSORPTION; INTESTINAL MUCOSA; METABOLIC CLEARANCE RATE; MODELS, ANIMAL; MODELS, BIOLOGICAL; PHARMACOKINETICS; SULFOTRANSFERASES;

EID: 84971574678     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-015-0351-6     Document Type: Review

References (282)

1. Bartholow M. Top 200 drugs of 2011. Pharmacy times. Available at: http://www.pharmacytimes.com/publications/issue/2012/July2012/Top-200-Drugs-of-2011. Accessed Jan 2013.
2. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15(1):110–5.
3. Rafil F, Franklin W, Heflich RH, Cerniglia CE. Reduction of nitroaromatic compounds by anaerobic bacteria isolated from the human gastrointestinal tract. Appl Environ Microbiol. 1991;57(4):962–8.
4. Nishimuta H, Houston JB, Galetin A. Hepatic, intestinal, renal, and plasma hydrolysis of prodrugs in human, cynomolgus monkey, dog, and rat: implications for in vitro–in vivo extrapolation of clearance of prodrugs. Drug Metab Dispos. 2014;42(9):1522–31.
5. Goldin BR. Intestinal microflora: metabolism of drugs and carcinogens. Ann Med. 1990;22(1):43–8.
6. McCabe M, Sane RS, Keith-Luzzi M, Xu J, King I, Whitcher-Johnstone A, et al. Defining the role of gut bacteria in the metabolism of deleobuvir: in vitro and in vivo studies. Drug Metab Dispos. 2015;43(10):1612–8.
7. Kaminsky LS, Zhang Q-Y. The small intestine as a xenobiotic-metabolizing organ. Drug Metab Dispos. 2003;31(12):1520–5.
8. Darwich AS, Aslam U, Ashcroft DM, Rostami-Hodjegan A. Meta-analysis of the turnover of intestinal epithelia in preclinical animal species and humans. Drug Metab Dispos. 2014;42(12):2016–22.
9. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “pie”. Drug Metab Dispos. 2006;34(5):880–6.
10. Yang J, Tucker GT, Rostami Hodjegan A. Cytochrome P450 3A expression and activity in the human small intestine. Clin Pharmacol Ther. 2004;76(4):391.
11. Kolars JC, Watkins P, Merion RM, Awni W. First-pass metabolism of cyclosporin by the gut. Lancet. 1991;338(8781):1488–90.
12. Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, McVicar JP, et al. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther. 1996;60(1):14–24.
13. von Richter O, Greiner B, Fromm MF, Fraser R, Omari T, Barclay ML, et al. Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique. Clin Pharmacol Ther. 2001;70(3):217–27.
14. Benet L, Cummins C, Wu C. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm. 2004;277(1):3–9.
15. Benet LZ. The drug transporter−metabolism alliance: uncovering and defining the interplay. Mol Pharm. 2009;6(6):1631–43.
16. Siissalo S, Heikkinen AT. In vitro methods to study the interplay of drug metabolism and efflux in the intestine. Curr Drug Metab. 2013;14(1):102–11.
17. Fagerholm U. Prediction of human pharmacokinetics: gut-wall metabolism. J Pharm Pharmacol. 2007;59(10):1335–43.
18. Hellriegel ET, Bjornsson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther. 1996;60(6):601–7.
19. Fahmi OA, Hurst S, Plowchalk D, Cook J, Guo F, Youdim K, et al. Comparison of different algorithms for predicting clinical drug–drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos. 2009;37(8):1658–66.
20. Fahmi OA, Maurer TS, Kish M, Cardenas E, Boldt S, Nettleton D. A combined model for predicting CYP3A4 clinical net drug–drug interaction based on CYP3A4 inhibition, inactivation, and induction determined in vitro. Drug Metab Dispos. 2008;36(8):1698–708.
21. Galetin A, Gertz M, Houston JB. Potential role of intestinal first-pass metabolism in the prediction of drug–drug interactions. Expert Opin Drug Metab Toxicol. 2008;4(7):909–22.
22. Galetin A, Gertz M, Houston JB. Contribution of intestinal cytochrome P450-mediated metabolism to drug–drug inhibition and induction interactions. Drug Metab Pharmacokinet. 2010;25(1):28–47.
23. Vieira ML, Kirby B, Ragueneau-Majlessi I, Galetin A, Chien J, Einolf H, et al. Evaluation of various static in vitro–in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug. Clin Pharmacol Ther. 2014;95(2):189–98.
24. Peters SA, Schroeder PE, Giri N, Dolgos H. Evaluation of the use of static and dynamic models to predict drug–drug interaction and its associated variability: impact on drug discovery and early development. Drug Metab Dispos. 2012;40(8):1495–507.
25. König J, Müller F, Fromm MF. Transporters and drug–drug interactions: important determinants of drug disposition and effects. Pharmacol Rev. 2013;65(3):944–66.
26. Müller F, Fromm MF. Transporter-mediated drug–drug interactions. Pharmacogenomics. 2011;12(7):1017–37.
27. Yoshida K, Maeda K, Sugiyama Y. Hepatic and intestinal drug transporters: prediction of pharmacokinetic effects caused by drug–drug interactions and genetic polymorphisms. Ann Rev Pharmacol Toxicol. 2013;53:581–612.
28. Zakeri-Milani P, Valizadeh H. Intestinal transporters: enhanced absorption through P-glycoprotein-related drug interactions. Expert Opin Drug Metab Toxicol. 2014;10(6):859–71.
29. Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22(1):11–23.
30. Komura H, Iwaki M. In vitro and in vivo small intestinal metabolism of CYP3A and UGT substrates in preclinical animals species and humans: species differences. Drug Metab Rev. 2011;43(4):476–98.
31. Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2006;2(6):875–94.
32. Tucker TG, Milne AM, Fournel-Gigleux S, Fenner KS, Coughtrie MW. Absolute immunoquantification of the expression of ABC transporters P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 2 in human liver and duodenum. Biochem Pharmacol. 2012;83(2):279–85.
33. Gröer C, Brück S, Lai Y, Paulick A, Busemann A, Heidecke C, et al. LC–MS/MS-based quantification of clinically relevant intestinal uptake and efflux transporter proteins. J Pharm Biomed Anal. 2013;85:253–61.
34. Shi S, Li Y. Interplay of drug-metabolizing enzymes and transporters in drug absorption and disposition. Curr Drug Metab. 2015;15(10):915–41.
35. Mohri K, Uesawa Y. Enzymatic activities in the microsomes prepared from rat small intestinal epithelial cells by differential procedures. Pharm Res. 2001;18(8):1232–6.
36. Sharer JE, Shipley LA, Vandenbranden MR, Binkley SN, Wrighton SA. Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey. Drug Metab Dispos. 1995;23(11):1231–41.
37. Kolars JC, Lown KS, Schmiedlin-Ren P, Ghosh M, Fang C, Wrighton SA, et al. CYP3A gene expression in human gut epithelium. Pharmacogenetics. 1994;4(5):247–59.
38. Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther. 1992;52(5):453–7.
39. Tsunoda SM, Velez RL, Moltke LL, Greenblatt DJ. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther. 1999;66(5):461–71.
40. Thummel KE, O’Shea D, Paine MF, Shen DD, Kunze KL, Perkins JD, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther. 1996;59(5):491–502.
41. Lennernäs H, Ahrenstedt Ö, Hällgren R, Knutson L, Ryde M, Paalzow LK. Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm Res. 1992;9(10):1243–51.
42. Lennernäs H, Nylander S, Ungell A-L. Jejunal permeability: a comparison between the Ussing Chamber technique and the single-pass perfusion in humans. Pharm Res. 1997;14(5):667–71.
43. van de Kerkhof EG, de Graaf IA, Groothuis GM. In vitro methods to study intestinal drug metabolism. Curr Drug Metab. 2007;8(7):658–75.
44. Lin JH, Chiba M, Baillie TA. Is the role of the small intestine in first-pass metabolism overemphasized? Pharmacol Rev. 1999;51(2):135–58.
45. Cubitt HE, Houston JB, Galetin A. Relative importance of intestinal and hepatic glucuronidation: impact on the prediction of drug clearance. Pharm Res. 2009;26(5):1073–83.
46. Galetin A, Gertz M, Houston JB. Contribution of intestinal cytochrome p450-mediated metabolism to drug–drug inhibition and induction interactions. Drug Metab Pharmacokinet. 2010;25(1):28–47.
47. Eeckhoudt S, Horsmans Y, Verbeeck R-K. Differential induction of midazolam metabolism in the small intestine and liver by oral and intravenous dexamethasone pretreatment in rat. Xenobiotica. 2002;32(11):975–84.
48. Kotegawa T, Laurijssens BE, von Moltke LL, Cotreau MM, Perloff MD, Venkatakrishnan K, et al. In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat. J Pharmacol Exper Ther. 2002;302(3):1228–37.
49. Kadono K, Akabane T, Tabata K, Gato K, Terashita S, Teramura T. Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor. Drug Metab Dispos. 2010;38(7):1230–7.
50. Kato M, Chiba K, Hisaka A, Ishigami M, Kayama M, Mizuno N, et al. The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoprotein-quantitative analysis based on information from the literature. Drug Metab Pharmacokinet. 2003;18(6):365–72.
51. Gertz M, Davis JD, Harrison A, Houston JB, Galetin A. Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. Curr Drug Metab. 2008;9(8):785–95.
52. Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther. 1995;57(5):485–91.
53. Farkas D, Oleson LE, Zhao Y, Harmatz JS, Zinny MA, Court MH, et al. Pomegranate juice does not impair clearance of oral or intravenous midazolam, a probe for cytochrome P450-3A activity: comparison with grapefruit juice. J Clin Pharmacol. 2007;47(3):286–94.
54. Kharasch ED, Walker A, Hoffer C, Sheffels P. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis. Clin Pharmacol Ther. 2004;76(5):452–66.
55. Kupferschmidt HH, Ha HR, Ziegler WH, Meier PJ, Krähenbühl S. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther. 1995;58(1):20–8.
56. Lundahl J, Regårdh C, Edgar B, Johnsson G. Effects of grapefruit juice ingestion—pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Clin Pharmacol. 1997;52(2):139–45.
57. Paine MF, Criss AB, Watkins PB. Two major grapefruit juice components differ in intestinal CYP3A4 inhibition kinetic and binding properties. Drug Metab Dispos. 2004;32(10):1146–53.
58. Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest. 1997;99(10):2545.
59. Rashid T, Martin U, Clarke H, Waller D, Renwick A, George C. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol. 1995;40(1):51–8.
60. Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressler D, Lee JW, et al. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther. 1997;62(1):41–9.
61. Guo L-Q, Fukuda K, Ohta T, Yamazoe Y. Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. Drug Metab Dispos. 2000;28(7):766–71.
62. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet. 1997;33(2):103–21.
63. Paine MF, Widmer WW, Hart HL, Pusek SN, Beavers KL, Criss AB, et al. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice: felodipine interaction. Am J Clinl Nutr. 2006;83(5):1097–105.
64. Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007;3(1):67–80.
65. Paine MF, Criss AB, Watkins PB. Two major grapefruit juice components differ in time to onset of intestinal CYP3A4 inhibition. J Pharmacol Exper Ther. 2005;312(3):1151–60.
66. Neuhoff S, Ungell A-L, Zamora I, Artursson P. pH-dependent bidirectional transport of weakly basic drugs across Caco-2 monolayers: implications for drug–drug interactions. Pharm Res. 2003;20(8):1141–8.
67. Ungell A-L. In vitro absorption studies and their relevance to absorption from the GI tract. Drug Dev Ind Pharm. 1997;23(9):879–92.
68. Neuhoff S, Ungell A-L, Zamora I, Artursson P. pH-Dependent passive and active transport of acidic drugs across Caco-2 cell monolayers. Eur J Pharm Sci. 2005;25(2):211–20.
69. Sjöberg Å, Lutz M, Tannergren C, Wingolf C, Borde A, Ungell A-L. Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. Eur J Pharm Sci. 2013;48(1):166–80.
70. Ungell AL, Nylander S, Bergstrand S, Sjöberg Å, Lennernäs H. Membrane transport of drugs in different regions of the intestinal tract of the rat. J Pharm Sci. 1998;87(3):360–6.
71. Li LY, Amidon GL, Kim JS, Heimbach T, Kesisoglou F, Topliss JT, et al. Intestinal metabolism promotes regional differences in apical uptake of indinavir: coupled effect of P-glycoprotein and cytochrome P450 3A on indinavir membrane permeability in rat. J Pharmacol Exp Ther. 2002;301(2):586–93.
72. Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: an overview. Adv Drug Deliv Rev. 2013;65(10):1340–56.
73. Murakami T, Takano M. Intestinal efflux transporters and drug absorption. Expert Opin Drug Metab Toxicol. 2008;4(7):923–39.
74. Zimmermann C, Gutmann H, Hruz P, Gutzwiller J-P, Beglinger C, Drewe J. Mapping of multidrug resistance gene 1 and multidrug resistance-associated protein isoform 1 to 5 mRNA expression along the human intestinal tract. Drug Metab Dispos. 2005;33(2):219–24.
75. Makhey VD, Guo A, Norris DA, Hu P, Yan J, Sinko PJ. Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm Res. 1998;15(8):1160–7.
76. Stephens R, O’Neill C, Warhurst A, Carlson G, Rowland M, Warhurst G. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J Pharmacol Exp Ther. 2001;296(2):584–91.
77. Englund G, Rorsman F, Rönnblom A, Karlbom U, Lazorova L, Gråsjö J, et al. 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(3):269–77.
78. Seithel A, Karlsson J, Hilgendorf C, Björquist A, Ungell A-L. Variability in mRNA expression of ABC-and SLC-transporters in human intestinal cells: comparison between human segments and Caco-2 cells. Eur J Pharm Sci. 2006;28(4):291–9.
79. Miao Q, Liu Q, Wang C, Meng Q, Guo X, Peng J, et al. Inhibitory effect of zinc on the absorption of JBP485 via the gastrointestinal oligopeptide transporter (PEPT1) in rats. Drug Metab Pharmacokinet. 2011;26(5):494–502.
80. Yamamoto-Furusho JK, Mendivil-Rangel EJ, Villeda-Ramirez MA, Fonseca-Camarillo G, Barreto-Zuniga R. Gene expression of carnitine organic cation transporters 1 and 2 (OCTN) is downregulated in patients with ulcerative colitis. Inflamm Bowel Dis. 2011;17(10):2205–6.
81. Tapaninen T, Neuvonen PJ, Niemi M. Grapefruit juice greatly reduces the plasma concentrations of the OATP2B1 and CYP3A4 substrate aliskiren. Clin Pharmacol Ther. 2010;88(3):339–42.
82. Herrera-Ruiz D, Wang Q, Gudmundsson OS, Cook TJ, Smith RL, Faria TN, et al. Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 in vitro cell culture model, and multiple human tissues. AAPS PharmSci. 2001;3(1):E9.
83. Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell A-L, Karlsson J. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab Dispos. 2007;35(8):1333–40.
84. De Waziers I, Cugnenc P, Yang C, Leroux J, Beaune P. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther. 1990;253(1):387–94.
85. Paine MF, Khalighi M, Fisher JM, Shen DD, Kunze KL, Marsh CL, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther. 1997;283(3):1552–62.
86. Zhang Q-Y, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS. Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos. 1999;27(7):804–9.
87. Thummel KE, Kunze KL, Shen DD. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev. 1997;27(2):99–127.
88. Gervot L, Carrière V, Costet P, Cugnenc P-H, Berger A, Beaune PH, et al. CYP3A5 is the major cytochrome P450 3A expressed in human colon and colonic cell lines. Environ Toxicol Pharmacol. 1996;2(4):381–8.
89. Kivistö KT, Griese E-U, Fritz P, Linder A, Hakkola J, Raunio H, et al. Expression of cytochrome P 450 3A enzymes in human lung: a combined RT-PCR and immunohistochemical analysis of normal tissue and lung tumours. Naunyn Schmiedebergs Arch Pharmacol. 1996;353(2):207–12.
90. van de Kerkhof EG, Ungell AL, Sjoberg AK, de Jager MH, Hilgendorf C, de Graaf IA, et al. Innovative methods to study human intestinal drug metabolism in vitro: precision-cut slices compared with ussing chamber preparations. Drug Metab Dispos. 2006;34(11):1893–902.
91. Bergheim I, Bode C, Parlesak A. Distribution of cytochrome P450 2C, 2E1, 3A4, and 3A5 in human colon mucosa. BMC Pharmacol Toxicol. 2005;5(1):4.
92. Darwich AS, Neuhoff S, Jamei M, Rostami-Hodjegan A. Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the “Advanced Dissolution, Absorption, Metabolism (ADAM)” model. Curr Drug Metab. 2010;11(9):716–29.
93. Berggren S, Lennernäs P, Ekelund M, Weström B, Hoogstraate J, Lennernäs H. Regional transport and metabolism of ropivacaine and its CYP3A4 metabolite PPX in human intestine. J Pharm Pharmacol. 2003;55(7):963–72.
94. Le Ferrec E, Chesne C, Artusson P, Brayden D, Fabre G, Gires P, et al. In vitro models of the intestinal barrier. Altern Lab Anim. 2001;29:649–68.
95. Pang KS. Modeling of intestinal drug absorption: roles of transporters and metabolic enzymes (for the Gillette Review Series). Drug Metab Dispos. 2003;31(12):1507–19.
96. Koster AS, Hofman GA, Frankhuijzen-Sierevogel A, Noordhoek J. Presystemic and systemic intestinal metabolism of fenoterol in the conscious rat. Drug Metab Dispos. 1985;13(4):464–70.
97. Saitoh H, Saikachi Y, Kobayashi M, Yamaguchi M, Oda M, Yuhki Y, et al. Limited interaction between tacrolimus and P-glycoprotein in the rat small intestine. Eur J Pharm Sci. 2006;28(1):34–42.
98. Doherty MM, Pang KS. Route-dependent metabolism of morphine in the vascularly perfused rat small intestine preparation. Pharm Res. 2000;17(3):291–8.
99. Ilett KF, Tee LB, Reeves PT, Minchin RF. Metabolism of drugs and other xenobiotics in the gut lumen and wall. Pharmacol Ther. 1990;46(1):67–93.
100. Hirayama H, Morgado J, Gasinska I, Pang K. Estimations of intestinal and liver extraction in the in vivo rat: studies on gentisamide conjugation. Drug Metab Dispos. 1990;18:580–7.
101. Hirayama H, Pang K. First-pass metabolism of gentisamide: influence of intestinal metabolism on hepatic formation of conjugates. Studies in the once-through vascularly perfused rat intestine-liver preparation. Drug Metab Dispos. 1990;18(5):580–7.
102. Xu X, Hirayama H, Pang KS. First-pass metabolism of salicylamide. Studies in the once-through vascularly perfused rat intestine-liver preparation. Drug Metab Dispos. 1989;17(5):556–63.
103. Mistry M, Houston JB. Quantitation of extrahepatic metabolism. Pulmonary and intestinal conjugation of naphthol. Drug Metab Dispos. 1985;13(6):740–5.
104. Mistry M, Houston JB. Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos. 1987;15(5):710–7.
105. Raoof AA, Augustijns PR, Verbeeck RK. In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism of propofol in the rat. Pharm Res. 1996;13(6):891–5.
106. Bohets H, Annaert P, Mannens G, Anciaux K, Verboven P, Meuldermans W, et al. Strategies for absorption screening in drug discovery and development. Curr Top Med Chem. 2001;1(5):367–83.
107. Lennernäs H, Renberg L, Hoffmann K-J, Regårdh C. Presystemic elimination of the beta-blocker pafenolol in the rat after oral and intraperitoneal administration and identification of a main metabolite in both rats and humans. Drug Metab Dispos. 1993;21(3):435–40.
108. Aoki M, Okudaira K, Haga M, Nishigaki R, Hayashi M. Contribution of rat pulmonary metabolism to the elimination of lidocaine, midazolam, and nifedipine. Drug Metab Dispos. 2010;38(7):1183–8.
109. Cui Z, He P, Luo M, Xia S, Wu M. Phenacetin-O-deethylation in extrahepatic tissues of rats. Eur J Drug Metab Pharmacokinet. 2002;27(2):107–11.
110. Li X, Xia S, Lv Y, He P, Han J, Wu M. Conjugation metabolism of acetaminophen and bilirubin in extrahepatic tissues of rats. Life Sci. 2004;74(10):1307–15.
111. Karlsson FH, Bouchene S, Hilgendorf C, Dolgos H, Peters SA. Utility of in vitro systems and preclinical data for the prediction of human intestinal first-pass metabolism during drug discovery and preclinical development. Drug Metab Dispos. 2013;41(12):2033–46.
112. Musther H, Olivares-Morales A, Hatley OJ, Liu B, Hodjegan AR. Animal versus human oral drug bioavailability: do they correlate? Eur J Pharm Sci. 2014;57:280–91.
113. Nishimuta H, Sato K, Mizuki Y, Yabuki M, Komuro S. Species differences in intestinal metabolic activities of cytochrome P450 isoforms between cynomolgus monkeys and humans. Drug Metab Pharmacokinet. 2011;26(3):300–6.
114. Mudra DR, Desino KE, Desai PV. In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp. Curr Drug Metab. 2011;12(8):750–73.
115. Barr WH, Riegelman S. Intestinal drug absorption and metabolism I: comparison of methods and models to study physiological factors of in vitro and in vivo intestinal absorption. J Pharm Sci. 1970;59(2):154–63.
116. Gugler R, Lain P, Azarnoff DL. Effect of portacaval shunt on the disposition of drugs with and without first-pass effect. J Pharmacol Exp Ther. 1975;195(3):416–23.
117. Lo M-W, Pond SM, Effeney DJ, Silber BM, Riegelman S, Tozer TN. Nonlinear formation of propranolol metabolites in dogs after portacaval transpositions. J Pharmacokinet Biopharm. 1984;12(4):401–12.
118. Doherty MM, Pang KS. First-pass effect: significance of the intestine for absorption and metabolism. Drug Chem Toxicol. 1997;20(4):329–44.
119. Castle S, Tucker G, Woods H, Underwood J, Nicholson C, Havler M, et al. Assessment of an in situ rat intestine preparation with perfused vascular bed for studying the absorption and first-pass metabolism of drugs. J Pharmacol Methods. 1985;14(4):255–74.
120. Matsuda Y, Konno Y, Satsukawa M, Kobayashi T, Takimoto Y, Morisaki K, et al. Assessment of intestinal availability of various drugs in the oral absorption process using portal vein-cannulated rats. Drug Metab Dispos. 2012;40(12):2231–8.
121. Kadono K, Koakutsu A, Naritomi Y, Terashita S, Tabata K, Teramura T. Comparison of intestinal metabolism of CYP3A substrates between rats and humans: application of portal-systemic concentration difference method. Xenobiotica. 2013;44(6):511–21.
122. Pang K, Yuen V, Fayz S, Te Koppele J, Mulder G. Absorption and metabolism of acetaminophen by the in situ perfused rat small intestine preparation. Drug Metab Dispos. 1986;14(1):102–11.
123. Pang KS, Cherry W, Ulm E. Disposition of enalapril in the perfused rat intestine-liver preparation: absorption, metabolism and first-pass effect. J Pharmacol Exp Ther. 1985;233(3):788–95.
124. Uhing MR, Kimura RE. The effect of surgical bowel manipulation and anesthesia on intestinal glucose absorption in rats. J Clin Invest. 1995;95(6):2790.
125. Yuasa H, Matsuda K, Watanabe J. Influence of anesthetic regimens on intestinal absorption in rats. Pharm Res. 1993;10(6):884–8.
126. Barthe L, Woodley J, Houin G. Gastrointestinal absorption of drugs: methods and studies. Fundam Clin Pharmacol. 1999;13(2):154–68.
127. Stappaerts J, Brouwers J, Annaert P, Augustijns P. In situ perfusion in rodents to explore intestinal drug absorption: challenges and opportunities. Int J Pharm. 2015;478(2):665–81.
128. Griffiths R, Lewis A, Jeffrey P. Models of drug absorption in situ and in conscious animals. In: Borchardt RT, Smith PL, Wilson, editors. Models for assessing drug absorption and metabolism. Springer: Berlin; 1996. p. 67–84.
129. Jeong EJ, Liu Y, Lin H, Hu M. In situ single-pass perfused rat intestinal model for absorption and metabolism. In: Caldwell GW, Zhengyin Y, editors. Optimization in drug discovery. Springer: Berlin; 2004. p. 65–76.
130. Schurgers N, Bijdendijk J, Tukker JJ, Crommelin DJ. Comparison of four experimental techniques for studying drug absorption kinetics in the anesthetized rat in situ. J Pharm Sci. 1986;75(2):117–9.
131. Cummins CL, Salphati L, Reid MJ, Benet LZ. 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(1):306–14.
132. Abuasal BS, Bolger MB, Walker DK, Kaddoumi A. In silico modeling for the nonlinear absorption kinetics of UK-343,664: a P-gp and CYP3A4 substrate. Mol Pharm. 2012;9(3):492–504.
133. Hu M, Sinko P, Johnson D, Amidon G. Membrane permeability parameters for some amino acids and β-lactam antibiotics: application of the boundary layer approach. J Theor Biol. 1988;131(1):107–14.
134. Balimane PV, Chong S, Morrison RA. Current methodologies used for evaluation of intestinal permeability and absorption. J Pharmacol Toxicol Methods. 2000;44(1):301–12.
135. Chiou WL, Barve A. Linear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Pharm Res. 1998;15(11):1792–5.
136. Chiou WL, Buehler PW. Comparison of oral absorption and bioavailability of drugs between monkey and human. Pharm Res. 2002;19(6):868–74.
137. Chiou WL, Jeong HY, Chung SM, Wu TC. Evaluation of using dog as an animal model to study the fraction of oral dose absorbed of 43 drugs in humans. Pharm Res. 2000;17(2):135–40.
138. Ward K, Nagilla R, Jolivette L. Comparative evaluation of oral systemic exposure of 56 xenobiotics in rat, dog, monkey and human. Xenobiotica. 2005;35(2):191–210.
139. Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, et al. Evaluation of rat intestinal absorption data and correlation with human intestinal absorption. Eur J Med Chem. 2003;38(3):233–43.
140. Riches Z, Stanley EL, Bloomer JC, Coughtrie MW. Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT “pie”. Drug Metab Dispos. 2009;37(11):2255–61.
141. Nishimuta H, Nakagawa T, Nomura N, Yabuki M. Species differences in hepatic and intestinal metabolic activities for 43 human cytochrome P450 substrates between humans and rats or dogs. Xenobiotica. 2013;43(11):948–55.
142. Furukawa T, Naritomi Y, Tetsuka K, Nakamori F, Moriguchi H, Yamano K, et al. Species differences in intestinal glucuronidation activities between humans, rats, dogs and monkeys. Xenobiotica. 2013;44(3):205–16.
143. Akabane T, Tabata K, Kadono K, Sakuda S, Terashita S, Teramura T. A comparison of pharmacokinetics between humans and monkeys. Drug Metab Dispos. 2010;38(2):308–16.
144. Takahashi M, Washio T, Suzuki N, Igeta K, Yamashita S. Investigation of the intestinal permeability and first-pass metabolism of drugs in cynomolgus monkeys using single-pass intestinal perfusion. Biol Pharm Bull. 2009;33(1):111–6.
145. Bueters T, Juric S, Sohlenius-Sternbeck A-K, Hu Y, Bylund J. Rat poorly predicts the combined non-absorbed and presystemically metabolized fractions in the human. Xenobiotica. 2012;43(7):607–16.
146. Komura H, Iwaki M. Species differences in in vitro and in vivo small intestinal metabolism of CYP3A substrates. J Pharm Sci. 2008;97(5):1775–800.
147. Jeong EJ, Liu Y, Lin H, Hu M. Species-and disposition model-dependent metabolism of raloxifene in gut and liver: role of UGT1A10. Drug Metab Dispos. 2005;33(6):785–94.
148. Teubner W, Meinl W, Florian S, Kretzschmar M, Glatt H. Identification and localization of soluble sulfotransferases in the human gastrointestinal tract. Biochem J. 2007;404:207–15.
149. Harbourt DE, Fallon JK, Ito S, Baba T, Ritter JK, Glish GL, et al. Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography–tandem mass spectrometry. Anal Chem. 2011;84(1):98–105.
150. Berry LM, Wollenberg L, Zhao Z. Esterase activities in the blood, liver and intestine of several preclinical species and humans. Drug Metab Lett. 2009;3(2):70–7.
151. Williams ET, Bacon JA, Bender DM, Lowinger JJ, Guo W-K, Ehsani ME, et al. Characterization of the expression and activity of carboxylesterases 1 and 2 from the beagle dog, cynomolgus monkey, and human. Drug Metab Dispos. 2011;39(12):2305–13.
152. Takara K, Ohnishi N, Horibe S, Yokoyama T. Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAs in rat small intestine. Drug Metab Dispos. 2003;31(10):1235–9.
153. Fasco MJ, Silkworth J, Dunbar DA, Kaminsky LS. Rat small intestinal cytochromes P450 probed by warfarin metabolism. Mol Pharmacol. 1993;43(2):226–33.
154. 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(6):1039–45.
155. Windmill KF, McKinnon RA, Zhu X, Gaedigk A, Grant DM, McManus ME. The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. Mut Res. 1997;376(1):153–60.
156. Zhang Q-Y, Wikoff J, Dunbar D, Kaminsky L. Characterization of rat small intestinal cytochrome P450 composition and inducibility. Drug Metab Dispos. 1996;24(3):322–8.
157. van de Kerkhof EG, de Graaf IA, de Jager MH, Meijer DK, Groothuis GM. Characterization of rat small intestinal and colon precision-cut slices as an in vitro system for drug metabolism and induction studies. Drug Metab Dispos. 2005;33(11):1613–20.
158. Mouly S, Paine MF. P-glycoprotein increases from proximal to distal regions of human small intestine. Pharm Res. 2003;20(10):1595–9.
159. Haller S, Schuler F, Lazic SE, Bachir-Cherif D, Krämer SD, Parrott NJ, et al. Expression profiles of metabolic enzymes and drug transporters in the liver and along the intestine of beagle dogs. Drug Metab Dispos. 2012;40(8):1603–11.
160. Rost D, Mahner S, Sugiyama Y, Stremmel W. Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine. Am J Physiol Gastrointest Liver Physiol. 2002;282(4):G720–6.
161. Mutch DM, Anderle P, Fiaux M, Mansourian R, Vidal K, Wahli W, et al. Regional variations in ABC transporter expression along the mouse intestinal tract. Physiol Genomics. 2004;17(1):11–20.
162. Enokizono J, Kusuhara H, Sugiyama Y. Regional expression and activity of breast cancer resistance protein (Bcrp/Abcg2) in mouse intestine: overlapping distribution with sulfotransferases. Drug Metab Dispos. 2007;35(6):922–8.
163. van Waterschoot RA, Schinkel AH. A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. Pharmacolog Rev. 2011;63(2):390–410.
164. Choo EF, Woolsey S, DeMent K, Ly J, Messick K, Qin A, et al. Use of transgenic mouse models to understand the oral disposition and drug–drug interaction potential of cobimetinib, a MEK inhibitor. Drug Metab Dispos. 2015;43(6):864–9.
165. Shen H-W, Jiang X-L, Gonzalez FJ, Yu A-M. Humanized transgenic mouse models for drug metabolism and pharmacokinetic research. Curr Drug Metab. 2011;12(10):997–1006.
166. Tang SC, Hendrikx JJ, Beijnen JH, Schinkel AH. Genetically modified mouse models for oral drug absorption and disposition. Curr Opin Pharmacol. 2013;13(6):853–8.
167. Cheung C, Gonzalez FJ. Humanized mouse lines and their application for prediction of human drug metabolism and toxicological risk assessment. J Pharmacol Exp Ther. 2008;327(2):288–99.
168. Scheer N, Wolf CR. Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications. Xenobiotica. 2014;44(2):96–108.
169. Salyers KL, Xu Y. Animal models for studying drug metabolizing enzymes and transporters. In: Zhang D, Surapaneni S, editors. ADME-enabling technologies in drug design and development. Wiley: London; 2012. p. 253.
170. Lin JH. Applications and limitations of genetically modified mouse models in drug discovery and development. Curr Drug Metab. 2008;9(5):419–38.
171. Mols R, Brouwers J, Schinkel AH, Annaert P, Augustijns P. Intestinal perfusion with mesenteric blood sampling in wild-type and knockout mice evaluation of a novel tool in biopharmaceutical drug profiling. Drug Metab Dispos. 2009;37(6):1334–7.
172. Muruganandan S, Sinal C. Mice as clinically relevant models for the study of cytochrome P450-dependent metabolism. Clin PharmacolTher. 2008;83(6):818–28.
173. Gonzalez FJ, Fang Z-Z, Ma X. Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity. Expert Opin Drug Metab Toxicol. 2015;11(6):869–81.
174. van Herwaarden AE, Wagenaar E, van der Kruijssen CM, van Waterschoot RA, Smit JW, Song JY, et al. Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism. J Clin Invest. 2007;117(11):3583–92.
175. van Waterschoot RA, ter Heine R, Wagenaar E, van der Kruijssen CM, Rooswinkel RW, Huitema AD, et al. Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol. 2010;160(5):1224–33.
176. van Waterschoot RA, Rooswinkel RW, Sparidans RW, van Herwaarden AE, Beijnen JH, Schinkel AH. Inhibition and stimulation of intestinal and hepatic CYP3A activity: studies in humanized CYP3A4 transgenic mice using triazolam. Drug Metab Dispos. 2009;37(12):2305–13.
177. Scheer N, Kapelyukh Y, McEwan J, Beuger V, Stanley LA, Rode A, et al. Modeling human cytochrome P450 2D6 metabolism and drug–drug interaction by a novel panel of knockout and humanized mouse lines. Mol Pharmacol. 2012;81(1):63–72.
178. Scheer N, Kapelyukh Y, Chatham L, Rode A, Buechel S, Wolf CR. Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines. Mol Pharmacol. 2012;82(6):1022–9.
179. van Waterschoot RA, van Herwaarden AE, Lagas JS, Sparidans RW, Wagenaar E, van der Kruijssen CM, et al. Midazolam metabolism in cytochrome P450 3A knockout mice can be attributed to up-regulated CYP2C enzymes. Mol Pharmacol. 2008;73(3):1029–36.
180. Scheer N, McLaughlin LA, Rode A, MacLeod AK, Henderson CJ, Wolf CR. Deletion of 30 murine cytochrome p450 genes results in viable mice with compromised drug metabolism. Drug Metab Dispos. 2014;42(6):1022–30.
181. Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of’bottom-up’vs’ top-down’recognition of covariates. Drug Metab Pharmacokinet. 2009;24(1):53–75.
182. Tsamandouras N, Rostami-Hodjegan A, Aarons L. Combining the ‘bottom up’and ‘top down’approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data. Br J Clin Pharmacol. 2015;79(1):48–55.
183. Kostewicz ES, Abrahamsson B, Brewster M, Brouwers J, Butler J, Carlert S, et al. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 2014;57:342–66.
184. Jones H, Chen Y, Gibson C, Heimbach T, Parrott N, Peters S, et al. Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective. Clin Pharmacol Ther. 2015;97(3):247–62.
185. Heikkinen AT, Fowler S, Gray L, Li J, Peng Y, Yadava P, et al. In vitro to in vivo extrapolation and physiologically based modeling of cytochrome P450 mediated metabolism in beagle dog gut wall and liver. Mol Pharm. 2013;10(4):1388–99.
186. Klees TM, Sheffels P, Dale O, Kharasch ED. Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos. 2005;33(3):303–11.
187. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004;32(4):447–54.
188. Baranczewski P, Stanczak A, Sundberg K, Svensson R, Wallin A, Jansson J, et al. Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol Rep. 2006;58(4):453–72.
189. Crespi CL. Xenobiotic-metabolizing Human Cells as Tools for Pharmacological and Toxocological Research. Adv Drug Res. 1995;26:180–237.
190. Proctor N, Tucker G, Rostami-Hodjegan A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica. 2004;34(2):151–78.
191. Bonkovsky HL, Hauri H-P, Marti U, Gasser R, Meyer UA. Cytochrome P450 of small intestinal epithelial cells. Immunochemical characterization of the increase in cytochrome P450 caused by phenobarbital. Gastroenterology. 1985;88(2):458–67.
192. Bruyère A, Declevès X, Bouzom F, Proust L, Martinet M, Walther B, et al. Development of an optimized procedure for the preparation of rat intestinal microsomes: comparison of hepatic and intestinal microsomal cytochrome P450 enzyme activities in two rat strains. Xenobiotica. 2009;39(1):22–32.
193. Cotreau MM, von Moltke LL, Beinfeld MC, Greenblatt DJ. Methodologies to study the induction of rat hepatic and intestinal cytochrome P450 3A at the mRNA, protein, and catalytic activity level. J Pharmacol Toxicol Methods. 2000;43(1):41–54.
194. Dawson JR, Bridges JW. Intestinal microsomal drug metabolism: A comparison of rat and guinea-pig enzymes, and of rat crypt and villous tip cell enzymes. Biochem Pharmacol. 1981;30(17):2415–20.
195. Galetin A, Houston JB. Intestinal and hepatic metabolic activity of five cytochrome P450 enzymes: impact on prediction of first-pass metabolism. J Pharmacol Exp Ther. 2006;318(3):1220–9.
196. Klippert P, Borm P, Noordhoek J. Prediction of intestinal first-pass effect of phenacetin in the rat from enzyme kinetic data: correlation with in in vivo data using mucosal blood flow. Biochem Pharmacol. 1982;31(15):2545–8.
197. Koster AS, Noordhoek J. Glucuronidation in the rat intestinal wall: Comparison of isolated mucosal cells, latent microsomes and activated microsomes. Biochem Pharm. 1983;32(5):895–900.
198. Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivistö KT. 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(3):172–83.
199. Watkins PB, Wrighton S, Schuetz E, Molowa D, Guzelian P. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. J Clin Invest. 1987;80(4):1029.
200. Weiser MM. Intestinal epithelial cell surface membrane glycoprotein synthesis I. An indicator of cellular differentiation. J Biol Chem. 1973;248(7):2536–41.
201. Zhang Z, Li Y, Shou M, Zhang Y, Ngui J, Stearns R, et al. Influence of different recombinant systems on the cooperativity exhibited by cytochrome P4503A4. Xenobiotica. 2004;34(5):473–86.
202. de Graaf IA, de Kanter R, de Jager MH, Camacho R, Langenkamp E, van de Kerkhof EG, et al. Empirical validation of a rat in vitro organ slice model as a tool for in vivo clearance prediction. Drug Metab Dispos. 2006;34(4):591–9.
203. de Graaf IA, Olinga P, de Jager MH, Merema MT, de Kanter R, van de Kerkhof EG, et al. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc. 2010;5(9):1540–51.
204. de Kanter R, Monshouwer M, Draaisma A, De Jager M, De Graaf I, Proost J, et al. Prediction of whole-body metabolic clearance of drugs through the combined use of slices from rat liver, lung, kidney, small intestine and colon. Xenobiotica. 2004;34(3):229–41.
205. de Kanter R, Tuin A, van de Kerkhof E, Martignoni M, Draaisma AL, de Jager MH, et al. A new technique for preparing precision-cut slices from small intestine and colon for drug biotransformation studies. J Pharmacol Toxicol Methods. 2005;51(1):65–72.
206. Groothuis GM, de Graaf IA. Precision-cut intestinal slices as in vitro tool for studies on drug metabolism. Curr Drug Metab. 2013;14(1):112–9.
207. Nejdfors P, Ekelund M, Jeppsson B, Weström B. Mucosal in vitro permeability in the intestinal tract of the pig, the rat, and man: species-and region-related differences. Scand J Gastroenterol. 2000;35(5):501–7.
208. Mariappan T, Singh S. Evidence of efflux-mediated and saturable absorption of rifampicin in rat intestine using the ligated loop and everted gut sac techniques. Mol Pharm. 2004;1(5):363–7.
209. Richter E, Strugala G. An all-glass perfusator for investigation of the intestinal transport and metabolism of foreign compounds in vitro. J Pharmacolog Methods. 1985;14(4):297–304.
210. Emoto C, Yamazaki H, Yamasaki S, Shimada N, Nakajima M, Yokoi T. Use of everted sacs of mouse small intestine as enzyme sources for the study of drug oxidation activities in vitro. Xenobiotica. 2000;30(10):971–82.
211. Arellano C, Philibert C, Vachoux C, Woodley J, Houin G. The metabolism of midazolam and comparison with other CYP enzyme substrates during intestinal absorption: in vitro studies with rat everted gut sacs. J Pharm Pharmaceut Sci. 2007;10(1):26–36.
212. Takemoto K, Yamazaki H, Tanaka Y, Nakajima M, Yokoi T. Catalytic activities of cytochrome P450 enzymes and UDP-glucuronosyltransferases involved in drug metabolism in rat everted sacs and intestinal microsomes. Xenobiotica. 2003;33(1):43–55.
213. Fisher R, Parsons D. A preparation of surviving rat small intestine for the study of absorption. The J Physiol. 1949;110(1–2):36–46.
214. Andlauer W, Kolb J, Fürst P. Isoflavones from tofu are absorbed and metabolized in the isolated rat small intestine. J Nutr. 2000;130(12):3021–7.
215. Andlauer W, Kolb J, Stehle P, Fürst P. Absorption and metabolism of genistein in isolated rat small intestine. J Nutr. 2000;130(4):843–6.
216. De Vries M, Hofman G, Koster A, Noordhoek J. Systemic intestinal metabolism of 1-naphthol. A study in the isolated vascularly perfused rat small intestine. Drug Metab Dispos. 1989;17(5):573–8.
217. Kavin H, Levin NW, Stanley MM. Isolated perfused rat small bowel: technic, studies of viability, glucose absorption. J Appl Physiol. 1967;22(3):604–11.
218. Larsson J, Pantzar N, Permert J, Olaison G. Integrity and metabolism of human ileal mucosa in vitro in the Ussing chamber. Acta Physiol Scand. 1998;162:47–56.
219. Gotoh Y, Kamada N, Momose D. The advantages of the Ussing Chamber in drug absorption studies. J Biomol Screen. 2005;10(5):517–23.
220. Polentarutti BI, Peterson AL, Sjöberg ÅK, Anderberg EKI, Utter LM, Ungell A-LB. Evaluation of viability of excised rat intestinal segments in the Ussing chamber: investigation of morphology, electrical parameters, and permeability characteristics. Pharm Res. 1999;16(3):446–54.
221. Lampen A, Christians U, Guengerich FP, Watkins PB, Kolars JC, Bader A, et al. Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos. 1995;23(12):1315–24.
222. Rogers SM, Back D, Orme M. Intestinal metabolism of ethinyloestradiol and paracetamol in vitro: studies using Ussing chambers. Br J Clin Pharmacol. 1987;23(6):727–34.
223. Lennernäs H. Animal data: the contributions of the Ussing Chamber and perfusion systems to predicting human oral drug delivery in vivo. Adv Drug Deliv Rev. 2007;59(11):1103–20.
224. Martignoni M, de Kanter R, Grossi P, Mahnke A, Saturno G, Monshouwer M. An in vivo and in vitro comparison of CYP induction in rat liver and intestine using slices and quantitative RT-PCR. Chem Biol Interact. 2004;151(1):1–11.
225. Martignoni M, Groothuis G, de Kanter R. Comparison of mouse and rat cytochrome P450-mediated metabolism in liver and intestine. Drug Metab Dispos. 2006;34(6):1047–54.
226. Worboys PD, Bradbury A, Houston JB. Kinetics of drug metabolism in rat liver slices III. Relationship between metabolic clearance and slice uptake rate. Drug Metab Dispos. 1997;25(4):460–7.
227. Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Prediction of intestinal first-pass drug metabolism. Curr Drug Metab. 2007;8(7):676–84.
228. Gertz M, Harrison A, Houston JB, Galetin A. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos. 2010;38(7):1147–58.
229. Bruyere A, Decleves X, Bouzom F, Ball K, Marques C, Treton X, et al. Effect of variations in the amounts of P-glycoprotein (ABCB1), BCRP (ABCG2) and CYP3A4 along the human small intestine on PBPK models for predicting intestinal first pass. Mol Pharm. 2010;7(5):1596–607.
230. Nishimuta H, Nakagawa T, Nomura N, Yabuki M. Significance of reductive metabolism in human intestine and quantitative prediction of intestinal first-pass metabolism by cytosolic reductive enzymes. Drug Metab Dispos. 2013;41(5):1104–11.
231. Naritomi Y, Nakamori F, Furukawa T, Tabata K. Prediction of hepatic and intestinal glucuronidation using in vitro–in vivo extrapolation. Drug Metab Pharmacokinet. 2015;30(1):21–9.
232. Wu B, Dong D, Hu M, Zhang S. Quantitative prediction of glucuronidation in humans using the in vitro-in vivo extrapolation approach. Curr Top Med Chem. 2013;13(11):1343–52.
233. Hatley O, Jones C, Galetin A, Rostami-Hodjegan A. The rat as a model for screening intestinal metabolism potential. Poster presentation at the 2012 AAPS annual meeting and exposition; october 14–17 2012; chicago. poster m1264; 2012.
234. Hatley OJD. Mechanistic prediction of intestinal first-pass metabolism using in vitro data in preclinical species and in man [PhD thesis]. Manchester: The University of Manchester; 2014.
235. Sohlenius-Sternbeck A-K, Orzechowski A. Characterization of the rates of testosterone metabolism to various products and of glutathione transferase and sulfotransferase activities in rat intestine and comparison to the corresponding hepatic and renal drug-metabolizing enzymes. Chem Biol Interact. 2004;148(1):49–56.
236. Peters SA. Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles. Clin Pharmacokinet. 2008;47(4):245–59.
237. Peters SA. Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis. Clin Pharmacokinet. 2008;47(4):261–75.
238. Chow EC, Pang SK. Why we need proper PBPK models to examine intestine and liver oral drug absorption. Curr Drug Metab. 2013;14(1):57–79.
239. Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev. 2001;50:S41–67.
240. Dokoumetzidis A, Kalantzi L, Fotaki N. Predictive models for oral drug absorption: from in silico methods to integrated dynamical models. Expert Opin Drug Metab Toxicol. 2007;3(4):491–505.
241. Ando H, Hisaka A, Suzuki H. A new physiologically based pharmacokinetic model for the prediction of gastrointestinal drug absorption: translocation model. Drug Metab Dispos. 2015;43(4):590–602.
242. Furukawa T, Nakamori F, Tetsuka K, Naritomi Y, Moriguchi H, Yamano K, et al. Quantitative prediction of intestinal glucuronidation of drugs in rats using in vitro metabolic clearance data. Drug Metab Pharmacokinet. 2012;27(2):171–80.
243. Furukawa T, Yamano K, Naritomi Y, Tanaka K, Terashita S, Teramura T. Method for predicting human intestinal first-pass metabolism of UGT substrate compounds. Xenobiotica. 2012;42(10):980–8.
244. Nakamori F, Naritomi Y, K-i Hosoya, Moriguchi H, Tetsuka K, Furukawa T, et al. Quantitative prediction of human intestinal glucuronidation effects on intestinal availability of UDP-glucuronosyltransferase substrates using in vitro data. Drug Metab Dispos. 2012;40(9):1771–7.
245. Nishimuta H, Sato K, Yabuki M, Komuro S. Prediction of the intestinal first-pass metabolism of CYP3A and UGT substrates in humans from in vitro data. Drug Metab Pharmacokinet. 2011;26(6):592–601.
246. Gertz M, Houston JB, Galetin A. Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. Drug Metab Dispos. 2011;39(9):1633–42.
247. Sohlenius-Sternbeck AK, Afzelius L, Prusis P, Neelissen J, Hoogstraate J, Johansson J, et al. Evaluation of the human prediction of clearance from hepatocyte and microsome intrinsic clearance for 52 drug compounds. Xenobiotica. 2010;40(9):637–49.
248. Obach RS. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos. 1999;27(11):1350–9.
249. Jones HM, Houston JB. Substrate depletion approach for determining in vitro metabolic clearance: time dependencies in hepatocyte and microsomal incubations. Drug Metab Dispos. 2004;32(9):973–82.
250. Tam D, Tirona RG, Pang SK. Segmental intestinal transporters and metabolic enzymes on intestinal drug absorption. Drug Metab Dispos. 2003;31(4):373–83.
251. Sun H, Pang SK. Physiological modeling to understand the impact of enzymes and transporters on drug and metabolite data and bioavailability estimates. Pharm Res. 2010;27(7):1237–54.
252. Pang KS, Chow EC. Commentary: theoretical predictions of flow effects on intestinal and systemic availability in physiologically based pharmacokinetic intestine models: the traditional model, segregated flow model, and QGut model. Drug Metab Dispos. 2012;40(10):1869–77.
253. Fan J, Chen S, Chow EC, Pang SK. PBPK modeling of intestinal and liver enzymes and transporters in drug absorption and sequential metabolism. Curr Drug Metab. 2010;11(9):743–61.
254. Heikkinen AT, Friedlein A, Lamerz J, Jakob P, Cutler P, Fowler S, et al. Mass spectrometry-based quantification of CYP enzymes to establish in vitro/in vivo scaling factors for intestinal and hepatic metabolism in beagle dog. Pharm Res. 2012;29(7):1832–42.
255. Heikkinen AT, Friedlein A, Matondo M, Hatley OJ, Petsalo A, Juvonen R, et al. Quantitative ADME proteomics–CYP and UGT enzymes in the beagle dog liver and intestine. Pharm Res. 2015;32(1):74–90.
256. Uchida Y, Ohtsuki S, Kamiie J, Terasaki T. Blood-brain barrier (BBB) pharmacoproteomics: reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain in mice. J Pharmacol Exp Ther. 2011;339(2):579–88.
257. Ballard P, Brassil P, Bui KH, Dolgos H, Petersson C, Tunek A, et al. The right compound in the right assay at the right time: an integrated discovery DMPK strategy. Drug Metab Rev. 2012;44(3):224–52.
258. Emoto C, Fukuda T, Cox S, Christians U, Vinks A. Development of a physiologically-based pharmacokinetic model for sirolimus: predicting bioavailability based on intestinal CYP3A content. CPT Pharmacometrics Syst Pharmacol. 2013;2(7):1–9.
259. Heikkinen AT, Baneyx G, Caruso A, Parrott N. Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates: an evaluation and case study using GastroPlus™. Eur J Pharm Sci. 2012;47(2):375–86.
260. Pal D, Mitra AK. MDR-and CYP3A4-mediated drug–drug interactions. J Neuroimmune Pharmacol. 2006;1(3):323–39.
261. Achour B, Russell MR, Barber J, Rostami-Hodjegan A. Simultaneous quantification of the abundance of several cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics. Drug Metab Dispos. 2014;42(4):500–10.
262. Sato Y, Nagata M, Tetsuka K, Tamura K, Miyashita A, Kawamura A, et al. Optimized methods for targeted peptide-based quantification of human uridine 5′-diphosphate-glucuronosyltransferases in biological specimens using liquid chromatography-tandem mass spectrometry. Drug Metab Dispos. 2014;42(5):885–9.
263. Oswald S, Gröer C, Drozdzik M, Siegmund W. Mass spectrometry-based targeted proteomics as a tool to elucidate the expression and function of intestinal drug transporters. AAPS J. 2013;15(4):1128–40.
264. Wang L, Prasad B, Salphati L, Chu X, Gupta A, Hop CE, et al. Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug Metab Dispos. 2015;43(3):367–74.
265. Harwood M, Neuhoff S, Carlson G, Warhurst G, Rostami-Hodjegan A. Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption. Biopharm Drug Dispos. 2013;34(1):2–28.
266. Thelen K, Dressman JB. Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol. 2009;61(5):541–58.
267. Thörn M, Finnström N, Lundgren S, Rane A, Lööf L. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol. 2005;60(1):54–60.
268. Uehara S, Murayama N, Nakanishi Y, Nakamura C, Hashizume T, Zeldin DC, et al. Immunochemical detection of cytochrome P450 enzymes in small intestine microsomes of male and female untreated juvenile cynomolgus monkeys. Xenobiotica. 2014;44(9):769–74.
269. Wang MZ, Wu JQ, Bridges AS, Zeldin DC, Kornbluth S, Tidwell RR, et al. Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine. Drug Metab Dispos. 2007;35(11):2067–75.
270. Borm PJ, Koster AS, Frankhuijzen-Sierevogel A, Noordhoek J. Comparison of two cell isolation procedures to study in vitro intestinal wall biotransformation in control and 3-methyl-cholanthrene pretreated rats. Cell Biochem Funct. 1983;1(3):161–7.
271. Behera D, Damre A, Varghese A, Addepalli V. In vitro evaluation of hepatic and extra-hepatic metabolism of coumarins using rat subcellular fractions: correlation of in vitro clearance with in vivo data. Drug Metab Drug Interact. 2008;23(3–4):329–50.
272. Pacifici G, Franchi M, Bencini C, Repetti F, Di Lascio N, Muraro G. Tissue distribution of drug-metabolizing enzymes in humans. Xenobiotica. 1988;18(7):849–56.
273. Gibbs JP, Yang J-S, Slattery JT. Comparison of human liver and small intestinal glutathione S-transferase-catalyzed busulfan conjugation in vitro. Drug Metab Dispos. 1998;26(1):52–5.
274. Shirkey R, Chakraborty J, Bridges J. An improved method for preparing rat small intestine microsomal fractions for studying drug metabolism. Anal Biochem. 1979;93:73–81.
275. Lawrence XY. An integrated model for determining causes of poor oral drug absorption. Pharm Res. 1999;16(12):1883–7.
276. Sawamoto T, Haruta S, Kurosaki Y, Higaki K, Kimura T. Prediction of the plasma concentration profiles of orally administered drugs in rats on the basis of gastrointestinal transit kinetics and absorbability. J Pharm Pharmacol. 1997;49(4):450–7.
277. Kimura T, Iwasaki N, Yokoe J-I, Haruta S, Yokoo Y, Ogawara K-I, et al. Analysis and prediction of absorption profile including hepatic first-pass metabolism of N-methyltyramine, a potent stimulant of gastrin release present in beer, after oral ingestion in rats by gastrointestinal-transit-absorption model. Drug Metab Dispos. 2000;28(5):577–81.
278. Remmel RP, Burchell B. Validation and use of cloned, expressed human drug-metabolizing enzymes in heterologous cells for analysis of drug metabolism and drug–drug interactions. Biochem Pharmacol. 1993;46(4):559–66.
279. Venkatakrishnan K, von Moltke LL, Harmatz JS, Crespi CL, Greenblatt DJ. Comparison between cytochrome P450 (CYP) content and relative activity approaches to scaling from cDNA-expressed CYPs to human liver microsomes: ratios of accessory proteins as sources of discrepancies between the approaches. Drug Metab Dispos. 2000;28(12):1493–504.
280. Sjögren E, Westergren J, Grant I, Hanisch G, Lindfors L, Lennernäs H, et al. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur J Pharm Sci. 2013;49(4):679–98.
281. Thelen K, Coboeken K, Willmann S, Burghaus R, Dressman JB, Lippert J. Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. J Pharm Sci. 2011;100(12):5324–45.
282. Parrott N, Lave T. Applications of physiologically based absorption models in drug discovery and development. Mol Pharm. 2008;5(5):760–75.