IDENTIFICATION OF THE UDP-GLUCURONOSYLTRANSFERASE ISOFORMS INVOLVED IN MYCOPHENOLIC ACID PHASE II METABOLISM

IDENTIFICATION OF THE UDP-GLUCURONOSYLTRANSFERASE ISOFORMS INVOLVED IN MYCOPHENOLIC ACID PHASE II METABOLISM

Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil is primarily metabolized by glucuronidation. The nature of UDP-glucuronosyltransferases (UGTs) involved in this pathway is still debated. The present study aimed at identifying unambiguously the UGT isoform...

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Published in:Drug metabolism and disposition Vol. 33; no. 1; pp. 139 - 146
Main Authors: Nicolas Picard, Damrong Ratanasavanh, Aurélie Prémaud, Yonnick Le Meur, Pierre Marquet
Format: Journal Article
Language:English
Published: United States American Society for Pharmacology and Experimental Therapeutics 01-01-2005
Subjects:
Animals
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Glucuronides - metabolism
Glucuronosyltransferase - antagonists & inhibitors
Glucuronosyltransferase - metabolism
Glucuronosyltransferase - physiology
Humans
Isoenzymes - antagonists & inhibitors
Isoenzymes - metabolism
Isoenzymes - physiology
Male
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
Mycophenolic Acid - metabolism
Rats
Rats, Sprague-Dawley
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Summary:Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil is primarily metabolized by glucuronidation. The nature of UDP-glucuronosyltransferases (UGTs) involved in this pathway is still debated. The present study aimed at identifying unambiguously the UGT isoforms involved in the production of MPA-phenyl-glucuronide (MPAG) and MPA-acylglucuronide (AcMPAG). A liquid chromatography-tandem mass spectrometry method allowing the identification and determination of the metabolites of mycophenolic acid was developed. The metabolites were characterized in urine and plasma samples from renal transplant patients under mycophenolate mofetil therapy and in vitro after incubation of mycophenolic acid with human liver (HLM), kidney (HKM), or intestinal microsomes (HIM). The UGT isoforms involved in MPAG or AcMPAG production were investigated using induced rat liver microsomes, heterologously expressed UGT (Supersomes), and chemical-selective inhibition of HLM, HKM, and HIM. The three microsomal preparations produced MPAG, AcMPAG, and two mycophenolate glucosides. Among the 10 UGT isoforms tested, UGT 1A9 was the most efficient for MPAG synthesis with a K m of 0.16 mM, close to that observed for HLM (0.18 mM). According to the chemical inhibition experiments, UGT 1A9 is apparently responsible for 55%, 75%, and 50% of MPAG production by the liver, kidney, and intestinal mucosa, respectively. Although UGT 2B7 was the only isoform producing AcMPAG in a significant amount, the selective inhibitor azidothymidine only moderately reduced this production (approximately -25%). In conclusion, UGT 1A9 and 2B7 were clearly identified as the main UGT isoforms involved in mycophenolic acid glucuronidation, presumably due to their high hepatic and renal expression.
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ISSN:0090-9556
1521-009X
DOI:10.1124/dmd.104.001651