Quantitative prediction of intestinal glucuronidation of drugs in rats using in vitro metabolic clearance data.

UDP-glucuronosyltransferase (UGT) is highly expressed in the small intestine and catalyzes the glucuronidation of small molecules, which may affect the oral bioavailability of drugs. However, no method of predicting the in vivo observed fraction of absorbed drug (F(a)F(g)) affected by UGT has yet been established. Here, we investigated the relationship between F(a)F(g) and in vitro clearance of nine UGT substrates (ketoprofen, tolcapone, telmisartan, raloxifene, entacapone, resveratrol, buprenorphine, quercetin, and ezetimibe) via UGT in intestinal microsomes (CL(int, UGT)) in rats. F(a)F(g) was calculated from pharmacokinetic parameters after intravenous and oral administration or using the portal-systemic concentration difference method, with values ranging from 0.027 (ezetimibe) to 1 (tolcapone). Glucuronides of model compounds were observed in the portal plasma after oral administration, with CL(int, UGT) values ranging from 57.8 (tolcapone) to 19,200 µL/min/mg (resveratrol). An inverse correlation between F(a)F(g) and CL(int, UGT) was observed for most compounds and was described using a simplified intestinal availability model reported previously. This model gave accurate predictions of F(a)F(g) values for three in-house compounds. Our results show that F(a)F(g) in rats is affected by UGT and can be predicted using CL(int, UGT). This work should hasten the development of a method to predict F(a)F(g) in humans.

[1]  Kenji Tabata,et al.  Quantitative Prediction of Intestinal Metabolism in Humans from a Simplified Intestinal Availability Model and Empirical Scaling Factor , 2010, Drug Metabolism and Disposition.

[2]  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.

[3]  T. Zhou,et al.  Sulfation of dietary flavonoids by human sulfotransferases , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[4]  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.

[5]  R. Obach,et al.  Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. , 2008, Chemical research in toxicology.

[6]  Z. Zuo,et al.  Intestinal and hepatic glucuronidation of flavonoids. , 2007, Molecular pharmaceutics.

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

[8]  Xuehua Jiang,et al.  Quantitative determination of isorhamnetin, quercetin and kaempferol in rat plasma by liquid chromatography with electrospray ionization tandem mass spectrometry and its application to the pharmacokinetic study of isorhamnetin. , 2007, Rapid communications in mass spectrometry : RCM.

[9]  C. Klaassen,et al.  Tissue- and Gender-Specific mRNA Expression of UDP-Glucuronosyltransferases (UGTs) in Mice , 2007, Drug Metabolism and Disposition.

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

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

[12]  V. Somoza,et al.  Metabolism and bioavailability of trans-resveratrol. , 2005, Molecular nutrition & food research.

[13]  M. Hayashi,et al.  Differentiation of organ availability by sequential and simultaneous analyses: intestinal conjugative metabolism impacts on intestinal availability in humans. , 2005, Journal of pharmaceutical sciences.

[14]  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.

[15]  F. Jamali,et al.  Effect of Gonadectomy and Hormones on Sex Differences in Ketoprofen Enantiomer Glucuronidation and Renal Excretion of Formed Glucuronides in the Rat , 2004, Pharmaceutical Research.

[16]  P. Maliakal,et al.  Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. , 2004, Journal of agricultural and food chemistry.

[17]  Guangping Chen,et al.  Tamoxifen induction of aryl sulfotransferase and hydroxysteroid sulfotransferase in male and female rat liver and intestine. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

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

[19]  J. Pezzuto,et al.  Human, Rat, and Mouse Metabolism of Resveratrol , 2002, Pharmaceutical Research.

[20]  J. Marier,et al.  Metabolism and Disposition of Resveratrol in Rats: Extent of Absorption, Glucuronidation, and Enterohepatic Recirculation Evidenced by a Linked-Rat Model , 2002, Journal of Pharmacology and Experimental Therapeutics.

[21]  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.

[22]  Y. Sugiyama,et al.  Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[23]  C. Rice-Evans,et al.  Resveratrol is absorbed in the small intestine as resveratrol glucuronide. , 2000, Biochemical and biophysical research communications.

[24]  C. Farley,et al.  Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663 , 2000, British journal of pharmacology.

[25]  T. Igarashi,et al.  Pharmacokinetics of 14C-Telmisartan (1) : Absorption, Distribution and Protein Binding of 14C-Telmisartan after a Single Oral Administration to Rats , 1999 .

[26]  T. Ebner,et al.  Disposition and chemical stability of telmisartan 1-O-acylglucuronide. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[27]  T. Seifert,et al.  Method to Estimate the Rate and Extent of Intestinal Absorption in Conscious Rats Using an Absorption Probe and Portal Blood Sampling , 1995, Pharmaceutical Research.

[28]  A. Vuorela,et al.  Metabolite profiles of two [14C]-labelled catechol O-methyltransferase inhibitors, nitecapone and entacapone, in rat and mouse urine and rat bile , 1994, European Journal of Drug Metabolism and Pharmacokinetics.

[29]  Tim Morris,et al.  Physiological Parameters in Laboratory Animals and Humans , 1993, Pharmaceutical Research.

[30]  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.

[31]  Robert L. Dedrick,et al.  Animal scale-up , 1973, Journal of Pharmacokinetics and Biopharmaceutics.

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

[33]  J. Paolini,et al.  Ezetimibe , 2005, Clinical pharmacokinetics.

[34]  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.

[35]  D. Jaeck,et al.  Interspecies scaling of tolcapone, a new inhibitor of catechol-O-methyltransferase (COMT). Use of in vitro data from hepatocytes to predict metabolic clearance in animals and humans. , 1996, Xenobiotica; the fate of foreign compounds in biological systems.

[36]  J. Taskinen,et al.  Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in rats and humans. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[37]  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.

[38]  D. Brewster,et al.  Biliary excretion, metabolism and enterohepatic circulation of buprenorphine. , 1981, Xenobiotica; the fate of foreign compounds in biological systems.

[39]  T Nakagawa,et al.  A pharmacokinetic analysis program (multi) for microcomputer. , 1981, Journal of pharmacobio-dynamics.