Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism.

Article Details

Citation

Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P

Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism.

Drug Metab Dispos. 2005 Jan;33(1):139-46. Epub 2004 Oct 6.

PubMed ID
15470161 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
Mycophenolate mofetilUDP-glucuronosyltransferase 1-9ProteinHumans
Unknown
Substrate
Details
Mycophenolate mofetilUDP-glucuronosyltransferase 2B7ProteinHumans
Unknown
Substrate
Details
Mycophenolic acidUDP-glucuronosyltransferase 1-9ProteinHumans
Unknown
Substrate
Details
Mycophenolic acidUDP-glucuronosyltransferase 2B7ProteinHumans
Unknown
Substrate
Details
Drug Reactions
Reaction
Details