Polymorphisms of UGT1A9 and UGT2B7 influence the pharmacokinetics of mycophenolic acid after a single oral dose in healthy Chinese volunteers.
OBJECTIVE
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 heterozygotes 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 of 1.5 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.
Pharmacogenetics Research group, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China.
Dong
D
Guo
Liang-Fang
LF
Pang
Yang
Y
Han
Hong
H
Yang
Guo
G
Wang
Zhi-Rong
ZR
Tan
Wei
W
Zhang
Hong-Hao
HH
Zhou
D000284:Administration, Oral; D044466:Asian People; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015810:Linkage Disequilibrium; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D000090264:UDP-Glucuronosyltransferase 1A9; D055815:Young Adult
D007166:Immunosuppressive Agents; C000715591:UGT1A9 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D009173:Mycophenolic Acid