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Review Article

In vitro and in vivo small intestinal metabolism of CYP3A and UGT substrates in preclinical animals species and humans: species differences

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Pages 476-498 | Received 15 Mar 2011, Accepted 13 Jun 2011, Published online: 23 Aug 2011

References

  • Abdallah, C., Besner, J. G., du Souich, P. (1995). Presystemic elimination of morphine in anesthetized rabbits: contribution of the intestine, liver, and lungs. Drug Metab Dispos 23:584–589.
  • Aiba, T., Takehara, Y., Okuno, M., Hashimoto, Y. (2003). Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats. Pharm Res 20:745–748.
  • Akabane, T., Tabata, K., Kadono, K., Sakuda, S., Terashita, S., Teramura, T. (2010). A comparison of pharmacokinetics between humans and monkeys. Drug Metab Dispos 38:308–316.
  • Arellano, C., Philibert, C., Vachoux, C., Woodley, J., Houin, G. (2007). 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 10:26–36.
  • Bae, S. K., Chung, W. S., Kim, E. J., Rhee, J. K., Kwon, J. W., Kim, W. B., et al. (2004). Pharmacokinetics of DA-7867, a new oxazolidione, after intravenous or oral administration to rats: intestinal first-pass effect. Antimicrob Agents Chemother 48:659–662.
  • Bae, S. K., Yang, K. H., Aryal, D. K., Kim, Y. G., Lee, M. G. (2009). Pharmacokinetics of amitriptyline and one of its metabolites, nortriptyline, in rats: little contribution of considerable hepatic first-pass effect to low bioavailability of amitriptyline due to great intestinal first-pass effect. J Pharm Sci 98:1587–1601.
  • Bernard, O., Guillemette, C. (2004). The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 32:775–778.
  • Bowalgaha, K., Miners, J. O. (2001). The glucuronidation of mycophenolic acid by human liver, kidney, and jejunum microsomes. Br J Clin Pharmacol 52:605–609.
  • Boxenbaum, H. (1980). Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 8:165–176.
  • Brand, W., Boersma, M. G., Bik, H., Hoek-van den Hil, E. F., Vervoort, J., Barron, D., et al. (2010). Phase II metabolism of hesperetin by individual UDP-glucuronosyltransferases and sulfotransferases and rat and human tissue samples. Drug Metab Dispos 38:617–625.
  • Brand, W., van der Wel, P. A., Rein, M. J., Barron, D., Williamson, G., van Bladeren, P. J., et al. (2008). Metabolism and transport of the citrus flavonoid hesperetin in Caco-2 cell monolayers. Drug Metab Dispos 36:1794–1802.
  • Carr, B., Norcross, R., Fang, Y., Lu, P., Rodrigues, A. D., Shou, M., Rushmore, T., et al. (2006). Characterization of the rhesus monkey CYP3A64 enzyme: species comparisons of CYP3A substrate specificity and kinetics using baculovirus-expressed recombinant enzymes. Drug Metab Dispos 34:1703–1712.
  • Chen, X., Yin, O. Q., Zuo, Z., Chow, M. S. (2005). Pharmacokinetics and modeling of quercetin and metabolites. Pharm Res 22:892–901.
  • Choi, Y. H., Kim, S. G., Lee, M. G. (2006). Dose-independent pharmacokinetics of metformin in rats: hepatic and gastrointestinal first-pass effects. J Pharm Sci 95:2543–2552.
  • Crespy, V., Morand, C., Manach, C., Besson, C., Demigne, C., Remesy, C. (1999). Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am J Physiol 277:G120–G126
  • Crowe, A., Bruelisauer, A., Duerr, L., Guntz, P., Lemaire, M. (1999). Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. Drug Metab Dispos 27:627–632.
  • Cubitt, H. E., Houston, J. B., Galetin, A. (2009). Relative importance of intestinal and hepatic glucuronidation-Impact on the prediction of drug clearance. Pharm Res 26:1073–1083.
  • de Graaf, I. A., de Kanter, R., de Jager, M. H., Camacho, R., Langenkamp, E., van de Kerkhof, E. G., et al. (2006). Empirical validation of a rat in vitro organ slice model as a tool for in vivo clearance prediction. Drug Metab Dispos 34;591–599.
  • de Kanter, R., Tuin, A., van de Kerkhof, E., Martignoni, M., Draaisma, A. L., de Jager, M. H., et al. (2005). A new technique for preparing precision-cut slices from small intestine and colon for drug biotransformation studies. J Pharmacol Toxicol Meth 51:65–72.
  • Dean, B. J., Chang, S., Elipe, M. V., Xia, Y. Q., Braun, M., Soli, E., et al. (2007). Metabolism of MK-0524, a prostaglandin D2 Receptor 1 antagonist, in microsomes and hepatocytes from preclinical species and humans. Drug Metab Dispos 35:283–292.
  • Doherty MM, Pang KS. (2000). Route-dependent metabolism of morphine in the vascularly perfused rat small intestine preparation. Pharm Res 17:291–298.
  • Dubey, R. K., Singh, J. (1988). Localization and characterization of drug-metabolizing enzymes along the villus-crypt surface of the rat small intestine—II. Conjugases. Biochem Pharmacol 37:177–184.
  • Ducharme, M. P., Warbasse, L. H., Edwards, D. J. (1995). Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 57:485–491.
  • Eeckhoudt, S. L., Horsmans, Y., Verbeeck, R. K. (2002). Differential induction of midazolam metabolism in the small intestine and liver by oral and intravenous dexamethasone pretreatment in rat. Xenobiotica 32:975–984.
  • Emoto, C., Yamazaki, H., Iketaki, H., Yamasaki, S., Satoh, T., Shimizu, R., et al. (2001). Cooperativity of α-naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human. Xenobiotica 31:265–275.
  • Emoto, C., Yamazaki, H., Yamasaki, S., Shimada, N., Nakajima, M., Yokoi, T. (2000a). Characterization of cytochrome P450 enzymes involved in drug oxidations in mouse intestinal microsomes. Xenobiotica 30:943–953.
  • Emoto, C., Yamazaki, H., Yamasaki, S., Shimada, N., Nakajima, M., Yokoi, T. (2000b). Use of everted sacs of mouse small intestine as enzyme sources for the study of drug oxidation activities in vitro. Xenobiotica 30:971–982.
  • Fisher, M. B., Campanale, K., Ackermann, B. L., Vandenbranden, M., Wrighton, S. A. (2000). In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos 28:560–566.
  • Fisher, M. B., Paine, M. F., Strelevitz, T. J., Wrighton, S. A. (2001). The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism. Drug Metab Rev 33:273–297.
  • Fisher, M. B., Vandenbranden, M., Findlay, K., Burchell, B., Thummel, K. E., Hall, S. D., et al. (2000). Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank. Pharmacogenetics 10:727–739.
  • Floren, L. C., Bekersky, I., Benet, L. Z., Mekki, Q., Dressler, D., Lee, J. W., et al. (1997). Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 62:41–49.
  • Fraser, D. J., Feyereisen, R., Harlow, G. R., Halpert, J. R. (1997). Isolation, heterologous expression, and functional characterization of a novel cytochrome P450 3A enzyme from a canine liver cDNA library. J Pharmacol Exp Ther 283:1425–1432.
  • Fromm, M. F., Busse, D., Kroemer, H. K., Eichelbaum, M. (1996). Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology 24:796–801.
  • Fujiwara, R., Nakajima, M., Oda, S., Yamanaka, H., Ikushiro, S., Sakaki, T., et al. (2010). Interactions between human UDP-glucuronosyltransferase (UGT) 2B7 and UGT1A enzymes. J Pharm Sci 99:442–454.
  • Fujiwara, R., Nakajima, M., Yamanaka, H., Nakamura, A., Katoh, M., Ikushiro, S., et al. (2007a). Effects of coexpression of UGT1A9 on enzymatic activities of human UGT1A isoforms. Drug Metab Dispos 35:747–757.
  • Fujiwara, R., Nakajima, M., Yamanaka, H., Katoh, M., Yokoi, T. (2007b). Interactions between human UGT1A1, UGT1A4, and UGT1A6 affect their enzymatic activities. Drug Metab Dispos 35:1782–1787.
  • Galetin, A., Houston, J. B. (2006). Intestinal and hepatic metabolic activity of five cytochrome P450 enzymes: impact on prediction of first-pass metabolism. J Pharmacol Exp Ther 318:1220–1229.
  • Gertz, M., Davis, J. D., Harrison, A., Houston, J. B., Galetin, A. (2008). Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. Curr Drug Metab 9;785–795.
  • Ghosal, A., Hapangama, N., Yuan, Y., Achanfuo-Yeboah, J., Iannucci, R., Chowdhury, S., et al. (2004). Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos 32:314–320.
  • Glaeser, H., Drescher, S., Hofmann, U., Heinkele, G., Somogyi, A. A., Eichelbaum, M., et al. (2004). Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans. Clin Pharmacol Ther 76:230–238.
  • Gomez, D. Y., Wacher, V. J., Tomlanovich, S. J., Herbert, M. F., Benet, L. Z. (1995). The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine. Clin Pharmacol Ther 58:15–19.
  • Gong, Q. H., Cho, J. W., Huang, T., Potter, C., Gholami, N., Basu, N. K., et al. (2001). Thirteen UDP glucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 11:357–368.
  • Gorski, J. C., Vannaprasaht, S., Hamman, M. A., Ambrosius, W. T., Bruce, M. A., Haehner-Daniels, B., et al. (2003). The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther 74:275–287.
  • Granvil, C. P., Yu, A. M., Elizondo, G., Akiyama, T. E., Cheung, C., Feigenbaum, L., et al. (2003). Expression of the human CYP3A4 gene in the small intestine of transgenic mice: in vitro metabolism and pharmacokinetics of midazolam. Drug Metab Dispos 31:548–558.
  • Gregory, P. A., Lewinsky, R. H., Gardner-Stephen, D. A., Mackenzie, P. I. (2004). Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. Toxicol App Pharmacol 199;354–363.
  • Guengerich, F. P., Martin, M. V., Beaune, P. H., Kremers, P., Wolff, T., Waxman, D. J. (1986). Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J Biol Chem 261:5051–5060.
  • Gupta, S. K., Bakran, A., Johnson, R. W., Rowland, M. (1988). Erythromycin enhances the absorption of cyclosporin. Br J Clin Pharmacol 25:401–402.
  • Gupta, M., Kovar, A., Meibohm, B. (2005). The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction. J Clin Pharmacol 45:987–1003.
  • Hanada, K., Ikemi, Y., Kukita, K., Mihara, K., Ogata, H. (2008). Stereoselective first-pass metabolism of verapamil in the small intestine and liver in rats. Drug Metab Dispos 36:2037–2042.
  • Hashimoto, Y., Sasa, H., Shimomura, M., Inui, K. (1998). Effects of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Pharm Res 15:1609–1613.
  • Hebert, M. F., Roberts, J. P., Prueksaritanont, T., Benet, L. Z. (1992). Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 52:453–457.
  • Higashikawa, F., Murakami, T., Kaneda, T., Kato, A., Takano, M. (1998). Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats. J Pharm Pharmacol 51:67–72.
  • Hirunpanich, V., Katagi, J., Sethabouppha, B., Sato, H. (2006). Demonstration of docosahexaenoic acid as a bioavailability enhancer for CYP3A substrates: in vitro and in vivo evidence using cyclosporin in rats. Drug Metab Dispos 34:305–310.
  • Hirunpanich, V., Murakoso, K., Sato, H. (2008). Inhibitory effect of docosahexaenoic acid (DHA) on the intestinal metabolism of midazolam: in vitro and in vivo studies in rats. Int J Pharm 351:133–143.
  • Ho, Y. F., Huang, D. K., Hsueh, W. C., Lai, M. Y., Yu, H. Y., Tsai, T. H. (2009). Effect of St. John’s wort extract on indinavir pharmacokinetics in rats: differentiation of intestinal and hepatic impacts. Life Sci 85:296–302.
  • Holtbecker, N., Fromm, M. F., Kroemer, H. K., Ohnhaus, E. E., Heidemann, H. (1996). The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism. Drug Metab Dispos 24:1121–1123.
  • Houston, J. B., Kenworthy, K. E. (2000). In vitro–in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. Drug Metab Dispos 28:246–254.
  • Ikemura, K., Urano, K., Matsuda, H., Mizutani, H., Iwamoto, T., Okuda, M. (2009). Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats: the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. J Pharmacol Exp Ther 328:249–255.
  • Itääho, K., Court, M. H., Uutela, P., Kostiainen, R., Radominska-Pandya, A., Finel, M. (2009). Dopamine is a low-affinity and high-specificity substrate for the human UDP-glucuronosyltransferease 1A10. Drug Metab Dispos 37:768–775.
  • Iwamoto, K., Klaassen, C. D. (1977). First-pass effect of morphine in rats. J Pharmacol Exp Ther 200:236–244.
  • Iwao, T., Inoue, K., Hayashi, Y., Yuasa, H., Watanabe, J. (2002). Metabolic extraction of nifedipine during absorption from the rat small intestine. Drug Metab Pharmacokinet 17:546–553.
  • Iwasaki, K., Murayama, N., Koizumi, R., Uno, Y., Yamazaki, H. (2010). Comparison of cytochrome P450 3A enzymes in cynomolgus monkeys and humans. Drug Metab Pharmacokinet 25:388–391.
  • Iwasaki, K., Uno, Y. (2009). Cynomolgus monkey CYPs: comparison with human CYPs. Xenobiotica 39:578–581.
  • Jäger, W., Correia, M. A., Bornheim, L. M., Mahnke, A., Hanstein, W. G., Xue, L., et al. (1999). Ethynylestradiol-mediated induction of hepatic CYP3A9 in female rats: implication for cyclosporine metabolism. Drug Metab Dispos 27:1505–1511.
  • Jeong, E. J., Liu, Y., Lin, H., Hu, M. (2005). Species- and disposition model-dependent metabolism of raloxifene in gut and liver: role of UGT1A10. Drug Metab Dispos 33:785–794.
  • Jetter, A., Kinzig-Schippers, M., Walchner-Bonjean, M., Hering, U., Bulitta, J., Schreiner, P., et al. (2002). Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 71:21–29.
  • Jin, M., Shimada, T., Yokogawa, K., Nomura, M., Kato, Y., Tsuji, A., et al. (2006). Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethasone. Int J Pharm 309:81–86.
  • Kaji, H., Kume, T. (2005). Regioselective glucuronidation of denopamine: marked species differences and identification of human UDP-glucuronosyltransferase isoform. Drug Metab Dispos 33:403–412.
  • Kanazu, T., Okamura, N., Yamaguchi, Y., Baba, T., Koike, M. (2005). Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug-drug interaction model rats. Xenobiotica 35:305–317.
  • Kanazu, T., Yamaguchi, Y., Okamura, N., Baba, T., Koike, M. (2004). Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. I: Evaluation of cynomolgus monkeys as surrogates for humans. Xenobiotica 34:391–402.
  • Kato, M., Chiba, K., Hisaka, A., Ishigami, M., Kayama, M., Nizuno, N., et al. (2003). The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoprotein. Quantitative analysis based on information from the literature. Drug Metab Pharmacokinet 18:365–372.
  • Kato, R., Yuasa, H., Inoue, K., Iwao, T., Tanaka, K., Ooi, K., et al. (2007). Effect of lactobacillus casei on the absorption of nifedipine from rat small intestine. Drug Metab Pharmacokinet 22:96–102.
  • Kemp, D. C., Fan, P. W., Stevens, J. C. (2002). Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Drug Metab Dispos 30:694–700.
  • Kolars, J. C., Awni, W. M., Merion, R. M., Watkins, P. B. (1991). First-pass metabolism of cyclosporine by the gut. Lancet 14:1488–1490.
  • Komura, H., Iwaki, M. (2008). Species differences in in vitro and in vivo small intestinal metabolism of CYP3A substrates. J Pharm Sci 97:1775–1800.
  • Komura, H., Yasuda, M., Yoshida, N. H., Sugiyama, Y. (2002). Species difference in nisoldipine oxidation activity in the small intestine. Drug Metab Pharmacokinet 17:427–436.
  • Kotegawa, T., Laurijssens, B. E., von Moltke, L. L., Cotreau, M. M., Perloff, M. D., Venkatakrishnan, K., et al. (2002). In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconzole and midazolam in the rat. J Pharmacol Exp Ther 302:1228–1237.
  • Kuroha, M., Kayaba, H., Kishimoto, S., Khalil, W. F., Shimoda, M., Kokue, E. (2002). Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs. J Pharm Sci 91:868–873.
  • Kuroiwa, Y., Yoshida, H., Ohshima, T., Shinohara, T., Ohguma, A., Kazuki, Y., et al. (2002). The use of chromosome-based vectors for animal transgenesis. Gene Ther 9:708–712.
  • Kurosawa, S., Uchida, S., Ito, Y., Yamada, S. (2009). Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats. Xenobiotica 39:162–170.
  • Kuze, J., Mutoh, T., Takenaka, T., Morisaki, K., Nakura, H., Hanioka, N., et al. (2009). Separate evaluation of intestinal and hepatic metabolism of three benzodiazepines in rats with cannulated portal and jugular veins: comparison with the profile in non-cannulated mice. Xenobiotica 39:871–880.
  • Kyokawa, Y., Nishibe, Y., Wakabayashi, M., Harauchi, T., Maruyama, T., Baba, T., et al. (2001). Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs. Chem Biol Interact 134:291–305.
  • Lampen, A., Christians, U., Bader, A., Hackbarth, I., Sewing, K. F. (1996a). Drug interactions and interindividual variability of ciclosporin metabolism in the small intestine. Pharmacology 52:159–168.
  • Lampen, A., Christians, U., Gonschior, A. K., Bader, A., Hackbarth, I., von Engelhardt, W., et al. (1996b). Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber. Br J Pharmacol 117:1730–1734.
  • Lampen, A., Zhang, Y., Hackbarth, I., Benet, L. Z., Sewing, K. F., Christians, U. (1998). Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. J Pharmacol Exp Ther 285:1104–1112.
  • Lee, J. I., Chaves-Gnecco, D., Amico, J. A., Kroboth, P. D., Wilson, J. W., Frye, R. F. (2002). Application of semisimultanenous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping. Clin Pharmacol Ther 72:718–728.
  • Lee, Y. H., Perry, B. A., Lee, H. S., Kunta, J. R., Sutyak, J. P., Sinko, P. J. (2001). Differentiation of gut and hepatic first-pass effect of drugs: 1. Studies of verapamil in ported dogs. Pharm Res 18:1721–1728.
  • Lin, Y. S., Dowling, A. L., Quigley, S. D., Farin, F. M., Zhang, J., Lamba, J., et al. (2002). Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 62:162–172.
  • Lindstrom, T. D., Whitaker, N. G., Whitaker, G. W. (1984). Disposition and metabolism of a new benzothiophene antiestrogen in rats, dogs, and monkeys. Xenobiotica 14:841–847.
  • Liu, Z., Hu, M. (2007). Natural polyphenol disposition via coupled metabolic pathways. Expert Opin Drug Metab Toxicol 3:389–406.
  • Loureiro, A. I., Bonifácio, M. J., Fernandes-Lopes, C., Almeida, L., Wright, L. C., Soares-Da-Silva, P. (2006). Human metabolism of nebicapone (BIA 3-202), a novel catechol-O-methyltransferase inhibitor: characterization of in vitro glucuronidation. Drug Metab Dispos 34:1856–1862.
  • Lown, K. S., Ghosh, M., Watkins, P. B. (1998). Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. Drug Metab Dispos 26:185–187.
  • Mackenzie, P. I., Bock, K. W., Burchell, B., Guillemette, C., Ikushiro, S., Iyanagi, T., et al. (2005). Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics 15:677–685.
  • Martignoni, M., Groothuis, G., de Kanter, R. (2006). Comparison of mouse and rat cytochrome P450-mediated metabolism in liver and intestine. Drug Metab Dispos 34:1047–1054.
  • Masica, A. L., Mayo, G., Wilkinson, G. R. (2004). In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam. Clin Pharmacol Ther 76:341–349.
  • Matsubara, T., Kim, H. J., Miyata, M., Shimada, M., Nagata, K., Yamazoe, Y. (2004). Isolation and characterization of a new major intestinal CYP3A form, CYP3A62, in the rat. J Pharmacol Exp Ther 309:1282–1290.
  • Mazoit, J. X., Sandouk, P., Scherrmann, J. M., Roche, A. (1990). Extrahepatic metabolism of morphine occurs in humans. Clin Pharmacol Ther 48:613–618.
  • Mealey, K. L., Jabbes, M., Spencer, E., Akey, J. M. (2008). Differential expression of CYP3A12 and CYP3A26 mRNAs in canine liver and intestine. Xenobiotica 38:1305–1312.
  • Miles, K. K., Kessler, F. K., Smith, P. C., Ritter, J. K. (2006). Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos 34:1632–1639.
  • Miners, J. O., Mackenzie, P. I., Knights, K. M. (2010). The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro–in vivo extrapolation of drug clearance and drug-drug interaction potential. Drug Metab Rev 42:196–208.
  • Mistry, M., Houston, J. B. (1987). Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metab Dispos 15:710–717.
  • Mizuma, T. (2009). Intestinal glucuronidation metabolism may have a greater impact on oral bioavailability than hepatic glucuronidation metabolism in humans: a study with raloxifene, substrate for UGT1A1, 1A8, 1A9, and 1A10. Int J Pharm 378:140–141.
  • Muirhead, G. J., Rance, D. J., Walker, D. K., Wastall, P. (2002). Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil. Br J Clin Pharmacol 53: 13–S20S
  • Murai, T., Samata, N., Iwabuchi, H., Ikeda, T. (2006). Human UDP-glucuronosyltransferase, UGT1A8, glucruonidates dihydrotestosterone to a monoglucuronide and further to a structurally novel diglucuronide. Drug Metab Dispos 34:1102–1108.
  • Murakami, T., Nakanishi, M., Yoshimori, T., Okamura, N., Norikura, R., Mizojiri, K. (2003). Separate assessment of intestinal and hepatic first-pass effects using a rat model with double cannulation of the portal and jugular veins. Drug Metab Pharmacokinet 18:252–260.
  • Muzeeb, S., Basha, S. J., Shashikumar, D., Mullangi, R., Srinivas, N. R. (2006). Glucuronidation of DRF-6574, hydroxyl metabolite of DRF-4367 (a novel COX-2 inhibitor) by pooled human liver, intestinal microsomes, and recombinant human UDP-glucuronosyltransferases (UGT): role of UGT1A1, 1A3, and 1A8. Eur J Drug Metab Pharmacokinet 31:299–309.
  • Nakamura, A., Nakajima, M., Yamanaka, H., Fujiwara, R., Yokoi, T. (2008). Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines. Drug Metab Dispos 36:1461–1464.
  • Nakanishi, Y., Matsushita, A., Matsuno, K., Iwasaki, K., Utoh, M., Nakamura, C., et al. (2010). Regional distribution of cytochrome P450 mRNA expression in the liver and small intestine of cynomolgus monkeys. Drug Metab Pharmacokinet 25:290–297.
  • Nishikawa, M., Ariyoshi, N., Kotani, A., Ishii, I., Nakamura, H., Nakasa, H., et al. (2004). Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam. Drug Metab Pharmacokinet 19:280–289.
  • Nishimura, T., Amano, N., Kubo, Y., Ono, M., Kato, Y., Fujita, H., et al. (2007). Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey. Drug Metab Dispos 35:1275–1284.
  • Nishimura, M., Koeda, A., Morikawa, H., Satoh, T., Narimatsu, S., Naito, S. (2009). Tissue-specific mRNA expression profiles of drug-metabolizing enzymes and transporters in the cynomolgus monkey. Drug Metab Pharmacokinet 24:139–144.
  • Nishimura, M., Yaguti, H., Yoshitsugu, H., Naito, S., Satoh, T. (2003). Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi 123:369–375.
  • Nishimuta, H., Sato, K., Mizuki, Y., Yabuki, M., Komuro, S. (2010). Prediction of the intestinal first-pass metabolism of CYP3 substrates in humans using cynomolgus monkeys. Drug Metab Dispos 38:1967–1975.
  • Ogasawara, A., Kume, T., Kazama, E. (2007). Effect of oral ketoconazole on intestinal first-pass effect of midazolam and fexofenadine in cynomolgus monkeys. Drug Metab Dispos 35:410–418.
  • Ohno, S., Nakajin, S. (2009). Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos 37:32–40.
  • Ohtsuka, T., Yoshikawa, T., Kozakai, K., Tsuneto, Y., Uno, Y., Utho, M., et al. (2010). Alprazolam as an in vivo probe for studing induction of CYP3A in cynomolgus monkeys. Drug Metab Dispos 38:1806–1813.
  • Osborne, R., Joel, S., Trew, D., Slevin, M. (1990). Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Cline Pharmacol Ther 47:12–19.
  • Oshimura, M., Katoh, M. (2008). Transfer of human artificial chromosome vectors into stem cells. Reprod Biomed Online 16:57–69.
  • Paine, M. F., Hart, H. L., Ludington, S. S., Haining, R. L., Rettie, A. E., Zeldin, D. C. (2006). The human intestinal cytochrome P450 “pie”. Drug Metab Dispos 34:880–886.
  • Paine, M. F., Khalighi, M., Fisher, J. M., Shen, D. D., Kunze, K. L., Marsh, C. L., et al. (1997). Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 283:1552–1562.
  • Paine, M. F., Shen, D. D., Kunze, K. L., Perkins, J. D., Marsh, C. L., McVicar, J. P., et al. (1996). First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther 60:14–24.
  • Patel, J. P., Korashy, H. M., EI-Kadi, A. O., Brocks, D. R. (2010). Effect of bile and lipids on the stereoselective metabolism of halofantrine by rat everted-intestinal sacs. Chirality 22:275–283.
  • Prueksaritanont, T., Gorham, L. M., Hochman, J. H., Tran, L. O., Vyas, K. P. (1996). Comparative studies of drug-metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. Drug Metab Dispos 24:634–642.
  • Ritter, J. K. (2007). Intestinal UGTs as potential modifiers of pharmacokinetics and biological responses to drugs and xenobiotics. Exp Opin Drug Toxicol 3:93–107.
  • Sakuda, S., Akabane, T., Teramura, T. (2006). Marked species differences in the bioavailability of midazolam in cynomolgus monkeys and humans. Xenobiotica 36:331–340.
  • Sandström, R., Knutson, T. W., Knutson, L., Jansson, B., Lennernäs, H. (1999). The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans. Br J Clin Pharmacol 48:180–189.
  • Schmider, J., Greenblatt, D. J., von Moltke, L. L., Harmatz, J. S., Shader, R. I. (1995). N-demethylation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isforms and effect of metabolic inhibitors. J Pharmacol Exp Ther 275:592–597.
  • Shelby, M. K., Cherrington, N. J., Vansell, N. R., Klaassen, C. D. (2003). Tissue mRNA expression of the rat UDP-glucuronosyltransferase gene family. Drug Metab Dispos 31:326–333.
  • Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., Guengerich, F. P. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens, and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423.
  • Shin, H. S., Bae, S. K., Lee, M. G. (2006). Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects. Int J Pharm 320:64–70.
  • Shiratani, H., Katoh, M., Nakajima, M., Yokoi, T. (2008). Species differences in UDP-glucuronosyltransferase activities in mice and rats. Drug Metab Dispos 36:1745–1752.
  • Silberberg, M., Morand, C., Mathevon, T., Besson, C., Manach, C., Scalbert, A., et al. (2006). The bioavailability of polyphenols is highly governed by the capacity of the intestine and of the liver to secrete conjugated metabolites. Eur J Nutr 45:88–96.
  • Soars, M. G., Burchell, B., Riley, R. J. (2002). In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther 301:382–390.
  • Strassburg, C. P., Kneip, S., Topp, J., Obermayer-Straub, P., Barut, A., Tukey, R. H., et al. (2000). Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine. J Biol Chem 275:36164–36171.
  • Strelevitz, T. J., Foti, R. S., Fisher, M. B. (2006). In vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearance. J Pharm Sci 95:1334–1341.
  • Tachibana, T., Kato, M., Takano, J., Sugiyama, Y. (2010). Predicting drug-drug interactions involving the inhibition of intestinal CYP3A and P-glycoprotein. Curr Drug Metab 11:762–777.
  • Takahashi, M., Washio, T., Suzuki, N., Igeta, K, Yamashita, S. (2009). The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans. J Pharm Sci 98:4343–4353.
  • Takanaga, H., Ohnishi, A., Murakami, H., Matsuo, H., Higuchi, S., Urae, A., et al. (2000). Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin Pharmacol Ther 67:201–214.
  • Takara, K., Ohnishi, N., Horibe, S., Yokoyama, T. (2003). Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAs in rat small intestine. Drug Metab Dispos 31:1235–1239.
  • Takemoto, K., Yamazaki, H., Tanaka, Y., Nakajima, M., Yokoi, T. (2003). Catalytic activities of cytochrome P450 enzymes and UDP-glucuronosyltransfereases involved in drug metabolism in rat everted sacs and intestinal microsomes. Xenobiotica 33:43–55.
  • Tang, L., Singh, R., Liu, Z., Hu, M. (2009). Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones. Mol Pharm 6:1466–1482.
  • Thummel, K. E., O’Shea, D., Paine, M. F., Shen, D. D., Kunze, K. L., Perkins, J. D., et al. (1996). Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther 59:491–502.
  • Tsunoda, S. M., Velez, R. L., von Moltke, L. L., Greenblatt, D. J. (1999). Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: effect of ketoconazole. Clin Pharmacol Ther 66:461–471.
  • Tsuruta, S., Nakamura, K., Arimori, K., Nakano, M. (1997). Inhibition of nifedipine metabolism in dogs by erythromycin: difference between the gut wall and the liver. J Pharm Pharmacol 49:1205–1210.
  • Uno, Y., Matsushita, A., Osada, N., Uehara, S., Kohara, S., Nagata, R., et al. (2010). Genetic variants of CYP3A4 and CYP3A5 in cynomolgus and rhesus macaques. Drug Metab Dispos 38:209–214.
  • van de Kerkhof, E. G., Ungell, A. L., Sjöberg, Å,. K., de Jager, M. H., Hilgendorf, C., de Graaf, I. A., et al. (2006). Innovative methods to study human intestinal drug metabolism in vitro: precision-cut slices compared with Ussing chamber preparations. Drug Metab Dispos 34:1893–1902.
  • van Herwaarden, A. E., van Waterschoot, R. A., Schinkel, A. H. (2009). How important is intestinal cytochrome P450 3A metabolism? Trends Pharmacol Sci 30:223–227.
  • van Herwaarden, A. E., Wagenaar, E., van der Kruijssen, C. M., van Waterschoot, R. A., Smit, J. W., et al. (2007). Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism. J Clin Invest 117:3583–3592.
  • van Waterschoot, R. A., Rooswinkel, R. W., Sparidans, R. W., van Herwaarden, A. E., Beijnen, J. H., Schinke, A. H. (2009). Inhibition and simulation of intestinal and hepatic CYP3A activity: studies in humanized CYP3A4 transgenic mice using triazolam. Drug Metab Dispos 37:2305–2313.
  • von Richter, O., Burk, O., Fromm, M. F., Thon, K. P., Eichelbaum, M., Kivistö, K. T. (2004). Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 75:172–183.
  • von Richter, O., Greiner, B., Fromm, M. F., Fraser, R., Omari, T., Barclay, M. L., et al. (2001). 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 70:217–227.
  • Wakui, Y., Yanagisawa, E., Ishibashi, E., Matsuzaki, Y., Takeda, S., Sasaki, H., et al. (1992). Determination of baicalin and baicalein in rat plasma by high-performance liquid chromatography wih electrochemical detection. J Chromatogr 575:131–136.
  • Watanabe, Y., Nakajima, M., Yokoi, T. (2002). Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. Drug Metab Dispos 30:1462–1469.
  • Watkins, P. B., Wrighton, S. A., Schuetz, E. G., Molowa, D. T., Guzelian, P. S. (1987). Identification of glucocorticoid-inducible cytochrome P-450 in the intestinal mucosa of rats and man. J Clin Invest 80:1029–1036.
  • Wilkinson, G. R. (2005). Drug metabolism and variability among patients in drug response. N Engl J Med 352:2211–2221.
  • Williams, J. A., Hyland, R., Jones, B. C., Smith, D. A., Hurst, S., Goosen, T. C., et al. (2004). Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCI/AUC) ratios. Drug Metab Dispos 32:1201–1208.
  • Wojnowski, L., Kamdem, L. K. (2006). Clinical implications of CYP3A polymorphisms. Exp Opin Drug Metab Toxicol 2:171–182.
  • Yamanaka, H., Nakajima, M., Katoh, M., Yokoi, T. (2007). Glucuronidation of thyroxine in human liver, jejunum, and kidney microsomes. Drug Metab Dispos 35:1642–1648.
  • Yang, J., Tucker, G. T., Rostami-Hodjegan, A. (2004). Cytochrome P450 3A expression and activity in the human small intestine. Clin Pharmacol Ther 76:391.
  • Yokomasu, A., Yano, I., Sato, E., Masuda, S., Katsura, T., Inui, K. (2008). Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everlimus in rats. Drug Metab Pharmacokinet 23:469–475.
  • Yoshisue, K., Nagayama, S., Shindo, T., Kawaguchi, Y. (2001). Effects of 5-fluorouracil on the drug-metabolizing enzymes of the small intestine and the consequent drug interaction with nifedipine in rats. J Pharmacol Exp Ther 297:1166–1175.
  • Zhang, Q. Y., Dunbar, D., Kaminsky, L. S. (2003). Characterization of mouse small intestinal cytochrome P450 expression. Drug Metab Dispos 31:1346–1351.
  • Zhang, Q. Y., Dunbar, D., Ostrowska, A., Zeisloft, S., Yang, J., Kaminsky, L. S. (1999). Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos 27:804–809.
  • Zhang, Q. Y., Fang, C., Zhang, J., Dunbar, D., Kaminsky, L., Ding, X. (2009b). An intestinal epithelium-specific cytochrome P450 (P450) reductase-knockout mouse model: direct evidence for a role of intestinal cytochrome P450s in first-pass clearance of oral nefedipine. Drug Metab Dispos 37:651–657.
  • Zhang, Q. Y., Kaminsky, L. S., Dunbar, D., Zhang, J., Ding, X. (2007). Role of small intestinal cytochromes P450 in the bioavailability of oral nifedipine. Drug Metab Dispos 35:1617–1623.
  • Zhang, L., Lin, G., Chang, Q., Zuo, Z. (2005). Role of intestinal first-pass metabolism of baicalein in its absorption process. Pharm Res 22:1050–1058.
  • Zhang, L., Lin, G., Zuo, Z. (2006). Involvement of UDP-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoid baicalein. Pharm Res 24:81–89.
  • Zhang, QY, Wikoff, J, Dunbar, D, Kaminsky, L. (1996). Characterization of rat small intestinal cytochrome P450 composition and inducibility. Drug Metab Dispos 24:322–328.
  • Zhang, H., Wu, X., Naraharisetti, S. B., Chung, F., Whittington, D., Mirfazaclian, A., et al. (2009a). Pregnancy does not increase CYP3A or P-glycoprotein activity in the non-human primate, Macaca nemestrina. J Pharmacol Exp Ther 330:586–595.
  • Zhu, Y., D’Agostino, J., Zhang, Q.-Y. (2011). Role of intestinal cytochrome P450 in modulating the bioavailability of oral lovastatin: insights from studies on the intestinal epithelium-specific P450 reductase knockout mouse. Drug Metab Dispos 39;939–943.
  • Zuber, R., Anzenbacherová, E., Anzenbacher, P. (2002). Cytochrome P450 and experimental models of drug metabolism. J Cell Mol Med 6:189–198.

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