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Eur J Clin Pharmacol (2013) 69:843849 DOI 10.1007/s00228-012-1409-0
PHARMACOKINETICS AND DISPOSITION
Polymorphisms of UGT1A9 and UGT2B7 influencethe pharmacokinetics of mycophenolic acid after a single oral dose in healthy Chinese volunteers
Dong Guo & Liang-Fang Pang & Yang Han & Hong Yang &
Guo Wang & Zhi-rong Tan & Wei Zhang & Hong-Hao Zhou
Received: 13 July 2012 /Accepted: 4 September 2012 /Published online: 10 October 2012 # Springer-Verlag 2012
AbstractPurpose To explore the impact of UDP-glucuronosyltransferase polymorphisms (UGT1A9-118(dT)9/10, UGT1A9 CI399T,
UGT1A9 C-440T and UGT2B7 G211T) on the pharmacokinetics of mycophenolic acid (MPA) in healthy Chinese volunteers. Methods We recruited ten healthy volunteers with no polymorphisms (control group), 11 homozygotes of mutants UGT1A9 CI399T and UGT1A9-118(dT)9/10, ten heterozy
gotes of UGT1A9 C440T and seven carriers of UGT2B7 211T from a total of 518 healthy Chinese volunteers. All the volunteers were orally administered a single dose of1.5 g mycophenolate mofetil (MMF) after an overnight fast. Plasma was then collected 72 h after MMF administration. MPA, MPA-7-O-glucuronide (MPAG) and its acylglucuronide (AcMPAG) were detected by ultra-pressure liquid chromatography with UV detection.
Results Compared with the control group, the UGT1A9 CI399T and UGT1A9-118(dT)9/10 mutant homozygotes had higher MPAG plasma concentrations. Subjects with UGT1A9-440TC had enhanced MPA exposure while carriers of UGT2B7 211T had higher concentrations of the toxic metabolite, AcMPAG.
Conclusions The current results indicate that UGT1A9 and UGT2B7 genotypes could significantly alter MPA pharmacokinetics in healthy Chinese volunteers after a single oral dose of MMF.
Keywords Polymorphisms . UGT1A9 . UGT2B7 . Mycophenolic acid . Pharmacokinetics
Introduction
Mycophenolate mofetil (MMF) is a widely used immunosuppressive agent for prevention of acute and chronic rejection after organ transplantation or with autoimmune diseases [1]. MMF is rapidly and extensively (95 %) hydrolyzed by esterases to the active metabolite mycophenolic acid (MPA). MPA non-competitively, selectively and reversibly inhibits the rate-limiting enzyme in the de novo synthesis of guanine nucleotides in lymphocytes, inosine monophosphate dehydrogenase type II (IMPDH-2) [2]. However, a narrow therapeutic index and broad interindividual variability in both beneficial effects and adverse reactions have been reported [3, 4]. Several studies reported that the interindividual variability in clinical response is mainly caused by variability in pharmacokinetics. Lower MPA C0 was associated with a higher risk of acute rejection episodes, while a high...