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

Intestinal first-pass metabolism has a great impact on the bioavailability of cytochrome P450 3A4 (CYP3A) and/or uridine 5′-diphosphate (UDP)-glucoronosyltranferase (UGT) substrates in humans. In vitro and in vivo intestinal metabolism studies are essential for clarifying pharmacokinetics in animal species and for predicting the effects of human intestinal metabolism. We review species differences in intestinal metabolism both in vitro and in vivo. Based on mRNA expression levels, the major intestinal CYP3A isoform is CYP3A4 for humans, CYP3A4 (3A8) for monkeys, CYP3A9 for rats, cyp3a13 for mice, and CYP3A12 for dogs. Additionally, the intestinal-specific UGT would be UGT1A10 for humans, UGT1A8 for monkeys, and UGT1A7 for rats. In vitro and in vivo intestinal metabolism of CYP3A substrates were larger in monkeys than in humans, although a correlation in intestinal availability between monkeys and humans has been reported. Little information is available regarding species differences in in vitro and in vivo UGT activities; however, UGT-mediated in vivo intestinal metabolism has been demonstrated for raloxifene in humans and for baicalein in rats. Further assessment of intestinal metabolism, particularly for UGT substrates, is required to clarify the entire picture of species differences.

[1]  J. Kolars,et al.  First-pass metabolism of cyclosporin by the gut , 1991, The Lancet.

[2]  T. Baba,et al.  Induction of intestinal cytochrome P450 (CYP3A) by rifampicin in beagle dogs. , 2001, Chemico-biological interactions.

[3]  H. Iwabuchi,et al.  HUMAN UDP-GLUCURONOSYLTRANSFERASE, UGT1A8, GLUCURONIDATES DIHYDROTESTOSTERONE TO A MONOGLUCURONIDE AND FURTHER TO A STRUCTURALLY NOVEL DIGLUCURONIDE , 2006, Drug Metabolism and Disposition.

[4]  J. Ritter,et al.  Characterization of Rat Intestinal Microsomal UDP-Glucuronosyltransferase Activity toward Mycophenolic Acid , 2006, Drug Metabolism and Disposition.

[5]  T. Kume,et al.  REGIOSELECTIVE GLUCURONIDATION OF DENOPAMINE: MARKED SPECIES DIFFERENCES AND IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ISOFORM , 2005, Drug Metabolism and Disposition.

[6]  Tetsuo Satoh,et al.  Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. , 2003, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan.

[7]  K. Pang,et al.  Route-Dependent Metabolism of Morphine in the Vascularly Perfused Rat Small Intestine Preparation , 2000, Pharmaceutical Research.

[8]  C. Klaassen,et al.  Tissue mRNA expression of the rat UDP-glucuronosyltransferase gene family. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[9]  R. de Kanter,et al.  COMPARISON OF MOUSE AND RAT CYTOCHROME P450-MEDIATED METABOLISM IN LIVER AND INTESTINE , 2006, Drug Metabolism and Disposition.

[10]  H. Glatt,et al.  Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples , 2010, Drug Metabolism and Disposition.

[11]  John D. Davis,et al.  Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. , 2008, Current drug metabolism.

[12]  E. J. Kim,et al.  Pharmacokinetics of DA-7867, a New Oxazolidinone, after Intravenous or Oral Administration to Rats: Intestinal First-Pass Effect , 2004, Antimicrobial Agents and Chemotherapy.

[13]  U. Hofmann,et al.  Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans , 2004, Clinical pharmacology and therapeutics.

[14]  C. Guillemette,et al.  Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. , 2005, Pharmacogenetics and genomics.

[15]  Glucuronidation of DRF-6574, hydroxy 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 , 2006, European Journal of Drug Metabolism and Pharmacokinetics.

[16]  S. Wrighton,et al.  Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank. , 2000, Pharmacogenetics.

[17]  H. Yamazaki,et al.  Catalytic activities of cytochrome P450 enzymes and UDP-glucuronosyltransferases involved in drug metabolism in rat everted sacs and intestinal microsomes , 2003, Xenobiotica; the fate of foreign compounds in biological systems.

[18]  L. Wojnowski,et al.  Clinical implications of CYP3A polymorphisms , 2006, Expert opinion on drug metabolism & toxicology.

[19]  M. Fromm,et al.  Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin , 1996, Hepatology.

[20]  A. D. Rodrigues,et al.  Characterization of the Rhesus Monkey CYP3A64 Enzyme: Species Comparisons of CYP3A Substrate Specificity and Kinetics Using Baculovirus-Expressed Recombinant Enzymes , 2006, Drug Metabolism and Disposition.

[21]  Kenji Tabata,et al.  A Comparison of Pharmacokinetics between Humans and Monkeys , 2010, Drug Metabolism and Disposition.

[22]  S. Yamashita,et al.  The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans. , 2009, Journal of pharmaceutical sciences.

[23]  W. Ambrosius,et al.  The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity , 2003, Clinical pharmacology and therapeutics.

[24]  D. Whittington,et al.  Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina , 2009, Journal of Pharmacology and Experimental Therapeutics.

[25]  B. Meibohm,et al.  The Clinical Pharmacokinetics of Phosphodiesterase‐5 Inhibitors for Erectile Dysfunction , 2005, Journal of clinical pharmacology.

[26]  T. Lindstrom,et al.  Disposition and metabolism of a new benzothiophene antiestrogen in rats, dogs and monkeys. , 1984, Xenobiotica; the fate of foreign compounds in biological systems.

[27]  H. Yamazaki,et al.  Genetic Variants of CYP3A4 and CYP3A5 in Cynomolgus and Rhesus Macaques , 2010, Drug Metabolism and Disposition.

[28]  Y. Horsmans,et al.  Differential induction of midazolam metabolism in the small intestine and liver by oral and intravenous dexamethasone pretreatment in rat , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[29]  T. Mizuma.  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. , 2009, International journal of pharmaceutics.

[30]  P. Watkins,et al.  Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. , 1987, The Journal of clinical investigation.

[31]  L. Benet,et al.  Tacrolimus oral bioavailability doubles with coadministration of ketoconazole , 1997, Clinical pharmacology and therapeutics.

[32]  K. Hanada,et al.  Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats , 2008, Drug Metabolism and Disposition.

[33]  M. Lee,et al.  Pharmacokinetics of sildenafil after intravenous and oral administration in rats: hepatic and intestinal first-pass effects. , 2006, International journal of pharmaceutics.

[34]  Z. Zuo,et al.  Pharmacokinetics and Modeling of Quercetin and Metabolites , 2005, Pharmaceutical Research.

[35]  K. Takara,et al.  Expression profiles of drug-metabolizing enzyme CYP3A and drug efflux transporter multidrug resistance 1 subfamily mRNAS in small intestine. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[36]  P. A. Gregory,et al.  Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. , 2004, Toxicology and applied pharmacology.

[37]  S. Ikushiro,et al.  Effects of Coexpression of UGT1A9 on Enzymatic Activities of Human UGT1A Isoforms , 2007, Drug Metabolism and Disposition.

[38]  P. Watkins,et al.  Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[39]  T. Mathevon,et al.  The bioavailability of polyphenols is highly governed by the capacity of the intestine and of the liver to secrete conjugated metabolites , 2006, European journal of nutrition.

[40]  J. Miners,et al.  The glucuronidation of mycophenolic acid by human liver, kidney and jejunum microsomes. , 2001, British journal of clinical pharmacology.

[41]  L. Benet,et al.  Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction , 1992, Clinical pharmacology and therapeutics.

[42]  Matthew W. Pennington,et al.  Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. , 2001, Pharmacogenetics.

[43]  Y. Sugiyama,et al.  Predicting drug-drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. , 2010, Current drug metabolism.

[44]  R. Singh,et al.  Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones. , 2009, Molecular pharmaceutics.

[45]  U. Christians,et al.  Drug interactions and interindividual variability of ciclosporin metabolism in the small intestine. , 1996, Pharmacology.

[46]  B. Burchell,et al.  In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. , 2002, The Journal of pharmacology and experimental therapeutics.

[47]  M. Lemaire,et al.  Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[48]  C. Manach,et al.  Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. , 1999, The American journal of physiology.

[49]  P. Kroboth,et al.  Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping , 2002, Clinical pharmacology and therapeutics.

[50]  M. Fromm,et al.  Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique , 2001, Clinical pharmacology and therapeutics.

[51]  Mary F Paine,et al.  THE HUMAN INTESTINAL CYTOCHROME P450 “PIE” , 2006, Drug Metabolism and Disposition.

[52]  M. Lee,et al.  Dose-independent pharmacokinetics of metformin in rats: Hepatic and gastrointestinal first-pass effects. , 2006, Journal of pharmaceutical sciences.

[53]  Shuji Ohno,et al.  Determination of mRNA Expression of Human UDP-Glucuronosyltransferases and Application for Localization in Various Human Tissues by Real-Time Reverse Transcriptase-Polymerase Chain Reaction , 2009, Drug Metabolism and Disposition.

[54]  A. V. van Herwaarden,et al.  How important is intestinal cytochrome P450 3A metabolism? , 2009, Trends in pharmacological sciences.

[55]  T. Kanazu,et al.  Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug–drug interaction model rats , 2005, Xenobiotica; the fate of foreign compounds in biological systems.

[56]  M. Manns,et al.  Polymorphic Gene Regulation and Interindividual Variation of UDP-glucuronosyltransferase Activity in Human Small Intestine* , 2000, The Journal of Biological Chemistry.

[57]  R. Fujiwara,et al.  Expression of UGT1A and UGT2B mRNA in Human Normal Tissues and Various Cell Lines , 2008, Drug Metabolism and Disposition.

[58]  Y. Sawada,et al.  Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects , 2000, Clinical pharmacology and therapeutics.

[59]  U. Christians,et al.  Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber , 1996, British journal of pharmacology.

[60]  M. Oshimura,et al.  The use of chromosome-based vectors for animal transgenesis , 2002, Gene Therapy.

[61]  Ji-Ying Song,et al.  Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism. , 2007, The Journal of clinical investigation.

[62]  K. Inui,et al.  Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats , 1998, Pharmaceutical Research.

[63]  L. Benet,et al.  Ethynylestradiol-mediated induction of hepatic CYP3A9 in female rats: implication for cyclosporine metabolism. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[64]  M. Hu,et al.  Natural polyphenol disposition via coupled metabolic pathways , 2007, Expert opinion on drug metabolism & toxicology.

[65]  J. Beijnen,et al.  Inhibition and Stimulation of Intestinal and Hepatic CYP3A Activity: Studies in Humanized CYP3A4 Transgenic Mice Using Triazolam , 2009, Drug Metabolism and Disposition.

[66]  A. Masica,et al.  In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam , 2004, Clinical pharmacology and therapeutics.

[67]  D. Shen,et al.  Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. , 1997, The Journal of pharmacology and experimental therapeutics.

[68]  D. Walker,et al.  Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil. , 2002, British journal of clinical pharmacology.

[69]  A. Galetin,et al.  Relative Importance of Intestinal and Hepatic Glucuronidation—Impact on the Prediction of Drug Clearance , 2009, Pharmaceutical Research.

[70]  J. Halpert,et al.  Isolation, heterologous expression and functional characterization of a novel cytochrome P450 3A enzyme from a canine liver cDNA library. , 1997, The Journal of pharmacology and experimental therapeutics.

[71]  Y. Sugiyama,et al.  Species difference in nisoldipine oxidation activity in the small intestine. , 2002, Drug metabolism and pharmacokinetics.

[72]  R. Foti,et al.  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. , 2006, Journal of pharmaceutical sciences.

[73]  M. Ducharme,et al.  Disposition of intravenous and oral cyclosporine after administration with grapefruit juice , 1995, Clinical pharmacology and therapeutics.

[74]  D. Greenblatt,et al.  N-demethylation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isoforms and effect of metabolic inhibitors. , 1995, The Journal of pharmacology and experimental therapeutics.

[75]  J B Houston,et al.  In vitro-in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[76]  R. Fujiwara,et al.  Interactions between Human UGT1A1, UGT1A4, and UGT1A6 Affect Their Enzymatic Activities , 2007, Drug Metabolism and Disposition.

[77]  M. Lee,et al.  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. , 2009, Journal of pharmaceutical sciences.

[78]  H. Yamazaki,et al.  Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys , 2010, Drug Metabolism and Disposition.

[79]  R. Iannucci,et al.  Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[80]  P. Anzenbacher,et al.  Cytochromes P450 and experimental models of drug metabolism , 2002, Journal of cellular and molecular medicine.

[81]  D. Dunbar,et al.  Characterization of human small intestinal cytochromes P-450. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[82]  Barry C. Jones,et al.  DRUG-DRUG INTERACTIONS FOR UDP-GLUCURONOSYLTRANSFERASE SUBSTRATES: A PHARMACOKINETIC EXPLANATION FOR TYPICALLY OBSERVED LOW EXPOSURE (AUCI/AUC) RATIOS , 2004, Drug Metabolism and Disposition.

[83]  K. Knights,et al.  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 , 2010, Drug metabolism reviews.

[84]  Olivier Bernard,et al.  The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[85]  H. Matsuda,et al.  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 , 2009, Journal of Pharmacology and Experimental Therapeutics.

[86]  C. Klaassen,et al.  First-pass effect of morphine in rats. , 1977, The Journal of pharmacology and experimental therapeutics.

[87]  G. Wilkinson,et al.  Drug metabolism and variability among patients in drug response. , 2005, The New England journal of medicine.

[88]  Yuan-qing Xia,et al.  Metabolism of MK-0524, a Prostaglandin D2 Receptor 1 Antagonist, in Microsomes and Hepatocytes from Preclinical Species and Humans , 2007, Drug Metabolism and Disposition.

[89]  D. Barron,et al.  Metabolism and Transport of the Citrus Flavonoid Hesperetin in Caco-2 Cell Monolayers , 2008, Drug Metabolism and Disposition.

[90]  Y. Uno,et al.  Regional distribution of cytochrome p450 mRNA expression in the liver and small intestine of cynomolgus monkeys. , 2010, Drug metabolism and pharmacokinetics.

[91]  M. G..  Human Metabolism , 2022, Nature.

[92]  D. Shen,et al.  First‐pass metabolism of midazolam by the human intestine , 1996, Clinical pharmacology and therapeutics.

[93]  S. Joel,et al.  Morphine and metabolite behavior after different routes of morphine administration: Demonstration of the importance of the active metabolite morphine‐6‐glucuronide , 1990, Clinical pharmacology and therapeutics.

[94]  S. Masuda,et al.  Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats. , 2008, Drug metabolism and pharmacokinetics.

[95]  D. Brocks,et al.  Effect of bile and lipids on the stereoselective metabolism of halofantrine by rat everted-intestinal sacs. , 2009, Chirality.

[96]  Y. Kato,et al.  Asymmetric Intestinal First-Pass Metabolism Causes Minimal Oral Bioavailability of Midazolam in Cynomolgus Monkey , 2007, Drug Metabolism and Disposition.

[97]  Amin Rostami-Hodjegan,et al.  Cytochrome P450 3A expression and activity in the human small intestine , 2004, Clinical pharmacology and therapeutics.

[98]  A. Kotani,et al.  Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam. , 2004, Drug metabolism and pharmacokinetics.

[99]  R. de Kanter,et al.  EMPIRICAL VALIDATION OF A RAT IN VITRO ORGAN SLICE MODEL AS A TOOL FOR IN VIVO CLEARANCE PREDICTION , 2006, Drug Metabolism and Disposition.

[100]  S. Uchida,et al.  Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[101]  M. Finel,et al.  Dopamine Is a Low-Affinity and High-Specificity Substrate for the Human UDP-Glucuronosyltransferase 1A10 , 2009, Drug Metabolism and Disposition.

[102]  K. Yoshisue,et al.  Effects of 5-fluorouracil on the drug-metabolizing enzymes of the small intestine and the consequent drug interaction with nifedipine in rats. , 2001, The Journal of pharmacology and experimental therapeutics.

[103]  D. Shen,et al.  Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism , 1996, Clinical pharmacology and therapeutics.

[104]  Y. Mizuki,et al.  Prediction of the Intestinal First-Pass Metabolism of CYP3A Substrates in Humans Using Cynomolgus Monkeys , 2010, Drug Metabolism and Disposition.

[105]  H. Yamazaki,et al.  Comparison of cytochrome P450 3A enzymes in cynomolgus monkeys and humans. , 2010, Drug metabolism and pharmacokinetics.

[106]  D. Greenblatt,et al.  Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole , 1999, Clinical pharmacology and therapeutics.

[107]  T. Kume,et al.  Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys , 2007, Drug Metabolism and Disposition.

[108]  T. Shimada,et al.  Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethasone. , 2006, International journal of pharmaceutics.

[109]  T. Murakami,et al.  Dose‐dependent Intestinal and Hepatic First‐pass Metabolism of Midazolam, a Cytochrome P450 3A Substrate with Differently Modulated Enzyme Activity in Rats , 1999, The Journal of pharmacy and pharmacology.

[110]  C. Abdallah,et al.  Presystemic elimination of morphine in anesthetized rabbits. Contribution of the intestine, liver, and lungs. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[111]  D. Dunbar,et al.  An Intestinal Epithelium-Specific Cytochrome P450 (P450) Reductase-Knockout Mouse Model: Direct Evidence for a Role of Intestinal P450s in First-Pass Clearance of Oral Nifedipine , 2009, Drug Metabolism and Disposition.

[112]  T. Akabane,et al.  Marked species differences in the bioavailability of midazolam in cynomolgus monkeys and humans , 2006, Xenobiotica; the fate of foreign compounds in biological systems.

[113]  S. Wrighton,et al.  The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism*† , 2001, Drug metabolism reviews.

[114]  H. Yamazaki,et al.  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. , 1994, The Journal of pharmacology and experimental therapeutics.

[115]  R. de Kanter,et al.  A new technique for preparing precision-cut slices from small intestine and colon for drug biotransformation studies. , 2005, Journal of pharmacological and toxicological methods.

[116]  J. Akey,et al.  Differential expression of CYP3A12 and CYP3A26 mRNAs in canine liver and intestine. , 2008, Xenobiotica; the fate of foreign compounds in biological systems.

[117]  Qing-Yu Zhang,et al.  Role of Intestinal Cytochrome P450 (P450) in Modulating the Bioavailability of Oral Lovastatin: Insights from Studies on the Intestinal Epithelium-Specific P450 Reductase Knockout Mouse , 2011, Drug Metabolism and Disposition.

[118]  M. Shimada,et al.  Isolation and Characterization of a New Major Intestinal CYP3A Form, CYP3A62, in the Rat , 2004, Journal of Pharmacology and Experimental Therapeutics.

[119]  U. Fuhr,et al.  Effects of grapefruit juice on the pharmacokinetics of sildenafil , 2002, Clinical pharmacology and therapeutics.

[120]  M. Nakajima,et al.  Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats , 2008, Drug Metabolism and Disposition.

[121]  A. Roche,et al.  Extrahepatic metabolism of morphine occurs in humans. , 1988, Clinical pharmacology and therapeutics.

[122]  M. Aburada,et al.  Determination of baicalin and baicalein in rat plasma by high-performance liquid chromatography with electrochemical detection. , 1992, Journal of chromatography.

[123]  H. Kusuhara,et al.  The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoprotein-quantitative analysis based on information from the literature. , 2003, Drug metabolism and pharmacokinetics.

[124]  Y. Uno,et al.  Cynomolgus monkey CYPs: a comparison with human CYPs , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[125]  L. Benet,et al.  The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine , 1995, Clinical pharmacology and therapeutics.

[126]  E. Schuetz,et al.  Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. , 2002, Molecular pharmacology.

[127]  H. Yamazaki,et al.  Characterization of cytochrome P450 enzymes involved in drug oxidations in mouse intestinal microsomes , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[128]  D. Dunbar,et al.  Characterization of mouse small intestinal cytochrome P450 expression. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[129]  Katsuhisa Inoue,et al.  Effect of Lactobacillus casei on the absorption of nifedipine from rat small intestine. , 2007, Drug metabolism and pharmacokinetics.

[130]  H. Lennernäs,et al.  The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans. , 1999, British journal of clinical pharmacology.

[131]  S. Wrighton,et al.  In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[132]  D. Dunbar,et al.  An Intestinal Epithelium-Specific Cytochrome P450 Reductase-Knockout Mouse Model: Direct Evidence for A Role of Intestinal Cytochromes P450 in First-pass Clearance of Oral Nifedipine , 2008 .

[133]  J. Ritter.  Intestinal UGTs as potential modifiers of pharmacokinetics and biological responses to drugs and xenobiotics , 2007, Expert opinion on drug metabolism & toxicology.

[134]  S. Ikushiro,et al.  Interactions between human UDP-glucuronosyltransferase (UGT) 2B7 and UGT1A enzymes. , 2010, Journal of pharmaceutical sciences.

[135]  A. Galetin,et al.  Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass Metabolism , 2006, Journal of Pharmacology and Experimental Therapeutics.

[136]  Jeffrey C Stevens,et al.  Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[137]  M. Rowland,et al.  Erythromycin enhances the absorption of cyclosporin. , 1988, British journal of clinical pharmacology.

[138]  M. Nakajima,et al.  Cooperativity of α-naphthoflavone in cytochrome P450 3A-dependent drug oxidation activities in hepatic and intestinal microsomes from mouse and human , 2001 .

[139]  H. Sato,et al.  Inhibitory effect of docosahexaenoic acid (DHA) on the intestinal metabolism of midazolam: in vitro and in vivo studies in rats. , 2007, International journal of pharmaceutics.

[140]  M. Nakajima,et al.  Glucuronidation of Thyroxine in Human Liver, Jejunum, and Kidney Microsomes , 2007, Drug Metabolism and Disposition.

[141]  P. Soares-da-Silva,et al.  Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation , 2006, Drug Metabolism and Disposition.

[142]  R. Dubey,et al.  Localization and characterization of drug-metabolizing enzymes along the villus-crypt surface of the rat small intestine--II. Conjugases. , 1988, Biochemical pharmacology.

[143]  Effects of St. John's wort extract on indinavir pharmacokinetics in rats: differentiation of intestinal and hepatic impacts. , 2009, Life sciences.

[144]  M. Nakajima,et al.  Troglitazone glucuronidation in human liver and intestine microsomes: high catalytic activity of UGT1A8 and UGT1A10. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[145]  Hitoshi Sato,et al.  DEMONSTRATION OF DOCOSAHEXAENOIC ACID AS A BIOAVAILABILITY ENHANCER FOR CYP3A SUBSTRATES: IN VITRO AND IN VIVO EVIDENCE USING CYCLOSPORIN IN RATS , 2006, Drug Metabolism and Disposition.

[146]  H. Boxenbaum.  Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoin , 1980, Journal of Pharmacokinetics and Biopharmaceutics.

[147]  M. Nakamura,et al.  Localization and Characterization , 1996 .

[148]  Huimin Lin,et al.  SPECIES- AND DISPOSITION MODEL-DEPENDENT METABOLISM OF RALOXIFENE IN GUT AND LIVER: ROLE OF UGT1A10 , 2005, Drug Metabolism and Disposition.

[149]  S. Narimatsu,et al.  Tissue-specific mRNA expression profiles of drug-metabolizing enzymes and transporters in the cynomolgus monkey. , 2009, Drug metabolism and pharmacokinetics.

[150]  M. D. de Jager,et al.  Innovative Methods to Study Human Intestinal Drug Metabolism in Vitro: Precision-Cut Slices Compared with Ussing Chamber Preparations , 2006, Drug Metabolism and Disposition.

[151]  D. Dunbar,et al.  Characterization of rat small intestinal cytochrome P450 composition and inducibility. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[152]  F. Gonzalez,et al.  Expression of the human CYP3A4 gene in the small intestine of transgenic mice: in vitro metabolism and pharmacokinetics of midazolam. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[153]  M. Iwaki,et al.  Species differences in in vitro and in vivo small intestinal metabolism of CYP3A substrates. , 2008, Journal of pharmaceutical sciences.

[154]  Oliver Burk,et al.  Cytochrome P450 3A4 and P‐glycoprotein Expression in Human Small Intestinal Enterocytes and Hepatocytes: A Comparative Analysis in Paired Tissue Specimens , 2004, Clinical pharmacology and therapeutics.

[155]  M. Fromm,et al.  The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[156]  H. Yamazaki,et al.  Use of everted sacs of mouse small intestine as enzyme sources for the study of drug oxidation activities in vitro , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[157]  K. Arimori,et al.  Inhibition of Nifedipine Metabolism in Dogs by Erythromycin: Difference between the Gut Wall and the Liver , 1997, The Journal of pharmacy and pharmacology.

[158]  D. Greenblatt,et al.  In Vitro, Pharmacokinetic, and Pharmacodynamic Interactions of Ketoconazole and Midazolam in the Rat , 2002, Journal of Pharmacology and Experimental Therapeutics.

[159]  Hideki Kayaba,et al.  Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs. , 2002, Journal of pharmaceutical sciences.

[160]  P. Sinko,et al.  Differentiation of Gut and Hepatic First-Pass Effect of Drugs: 1. Studies of Verapamil in Ported Dogs , 2001, Pharmaceutical Research.

[161]  Z. Zuo,et al.  Involvement of UDP-Glucuronosyltransferases in the Extensive Liver and Intestinal First-Pass Metabolism of Flavonoid Baicalein , 2006, Pharmaceutical Research.

[162]  G. Houin,et al.  The metabolism of midazolam and comparison with other CYP enzyme substrates during intestinal absorption: in vitro studies with rat everted gut sacs. , 2007, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[163]  D. Dunbar,et al.  Role of Small Intestinal Cytochromes P450 in the Bioavailability of Oral Nifedipine , 2007, Drug Metabolism and Disposition.

[164]  Z. Zuo,et al.  Role of Intestinal First-Pass Metabolism of Baicalein in its Absorption Process , 2005, Pharmaceutical Research.

[165]  D. Waxman,et al.  Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. , 1986, The Journal of biological chemistry.

[166]  S. Narimatsu,et al.  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 , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[167]  J. Houston,et al.  Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[168]  U. Christians,et al.  Metabolism and transport of the macrolide immunosuppressant sirolimus in the small intestine. , 1998, The Journal of pharmacology and experimental therapeutics.

[169]  K. Mizojiri,et al.  Separate assessment of intestinal and hepatic first-pass effects using a rat model with double cannulation of the portal and jugular veins. , 2003, Drug metabolism and pharmacokinetics.

[170]  Y. Hashimoto,et al.  Poor Correlation Between Intestinal and Hepatic Metabolic Rates of CYP3A4 Substrates in Rats , 2003, Pharmaceutical Research.

[171]  T. Kanazu,et al.  Model for the drug–drug interaction responsible for CYP3A enzyme inhibition. I: evaluation of cynomolgus monkeys as surrogates for humans , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[172]  Katsuhisa Inoue,et al.  Metabolic extraction of nifedipine during absorption from the rat small intestine. , 2002, Drug metabolism and pharmacokinetics.

[173]  M. Oshimura,et al.  Transfer of human artificial chromosome vectors into stem cells. , 2008, Reproductive biomedicine online.

[174]  J. Hochman,et al.  Comparative studies of drug-metabolizing enzymes in dog, monkey, and human small intestines, and in Caco-2 cells. , 1996, Drug metabolism and disposition: the biological fate of chemicals.