Identification of Human UDP-Glucuronosyltransferase Isoform(s) Responsible for the Glucuronidation of 2-(4-Chlorophenyl)-5-(2-Furyl)-4-Oxazoleacetic Acid (TA-1801A)

doi:10.2133/dmpk.20.212

Drug Metabolism and Pharmacokinetics

Volume 20, Issue 3, 2005, Pages 212-218

https://doi.org/10.2133/dmpk.20.212 Get rights and content

Summary:

We characterized the hepatic and intestinal UDP-glucuronosyltransferase (UGT) isoform(s) responsible for the glucuronidation of 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetic acid (TA-1801A) in humans through several in vitro mechanistic studies. Assessment of a panel of recombinant UGT isoforms revealed the TA-1801A glucuronosyltransferase activity of UGT1A1, UGT1A3, UGT1A7, UGT1A9, and UGT2B7. Kinetic analyses of the TA-1801A glucuronidation by recombinant UGT1A1, UGT1A3, UGT1A9, and UGT2B7 showed that the K_m value for UGT2B7 was apparently consistent with those in human liver and jejunum microsomes. The TA-1801A glucuronosyltransferase activity in human liver microsomes was inhibited by bilirubin (typical substrate for UGT1A1), propofol (typical substrate for UGT1A9), diclofenac (substrate for UGT1A9 and UGT2B7), and genistein (substrate for UGT1A1, UGT1A3, and UGT1A9). The inhibition by bilirubin, propofol, and diclofenac of the TA-1801A glucuronidation was less pronounced in jejunum microsomes than liver microsomes, suggesting that the contribution of UGT1A1, UGT1A9, and UGT2B7 to the TA-1801A glucuronidation is smaller in the intestine than the liver. In contrast, genistein strongly inhibited the TA-1801A glucuronosyltrans-ferase activity in both human liver and jejunum microsomes. These results suggest that the glucuronidation of TA-1801A is mainly catalyzed by UGT1A1, UGT1A9, and UGT2B7 in the liver, and by UGT1A1, UGT1A3, and UGT2B7 in the intestine in humans.

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Regular ArticleIdentification of Human UDP-Glucuronosyltransferase Isoform(s) Responsible for the Glucuronidation of 2-(4-Chlorophenyl)-5-(2-Furyl)-4-Oxazoleacetic Acid (TA-1801A)

Summary:

Drug Metab. Pharmacokin.

Toxicology

Chem. Biol. Interact.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Arch. Biochem. Biophys.

Synthesis of ethyl 2-(4-chlorophenyl)-5-(2-furyl)-4-oxazoleacetate, a hypolipidemic agent, and related compounds

J. Med. Chem.

Predicting human drug glucuronidation parameters: application of in vitro and in silico modeling approaches

Annu. Rev. Pharmacol. Toxicol.

Human UDP-glucuronosyltransferase: metabolism, expression, and disease

Annu. Rev. Pharmacol. Toxicol.

UDP-glucuronosyltransferases

Curr. Drug Metab.

Regular Article
Identification of Human UDP-Glucuronosyltransferase Isoform(s) Responsible for the Glucuronidation of 2-(4-Chlorophenyl)-5-(2-Furyl)-4-Oxazoleacetic Acid (TA-1801A)