Document Detail

Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism.
MedLine Citation:
PMID:  15470161     Owner:  NLM     Status:  MEDLINE    
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.
Nicolas Picard; Damrong Ratanasavanh; Aurélie Prémaud; Yonnick Le Meur; Pierre Marquet
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-10-06
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  33     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-20     Completed Date:  2005-04-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  139-46     Citation Subset:  IM    
Department of Pharmacology-Toxicology, University Hospital, 87042 Limoges, France.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Glucuronides / metabolism
Glucuronosyltransferase / antagonists & inhibitors,  metabolism*,  physiology
Isoenzymes / antagonists & inhibitors,  metabolism,  physiology
Microsomes, Liver / drug effects,  enzymology
Mycophenolic Acid / metabolism*
Rats, Sprague-Dawley
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Glucuronides; 0/Isoenzymes; 24280-93-1/Mycophenolic Acid; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Trans-3'-hydroxycotinine O- and N-glucuronidations in human liver microsomes.
Next Document:  Perioperative use of beta-blockers remains low: experience of a single Canadian tertiary institution...