Pharmacokinetics of mycophenolate mofetil and its glucuronide metabolites in healthy volunteers.
We previously reported that polymorphisms in the UGT2B7 and UGT1A9 genes are associated with significant alteration in the disposition of mycophenolic acid (MPA) in healthy volunteers.


OBJECTIVE
This study further evaluates the impact of genetic polymorphisms at the UGT1A1, UGT1A7 and ABCC2 loci.


METHODS
Genetic analyses of five UGT candidate genes and ABCC2 were completed on 47 healthy subjects who received a single dose of 1.5 g mycophenolate mofetil and completed a 12-h pharmacokinetic profile.


RESULTS
Multivariate analyses indicate that the ABCC2 -24T promoter polymorphism is associated with a 25% increase in acyl mycophenolic acid phenolic glucuronide level. Subjects with combined ABCC2 -24T and UGT1A9*3 genotypes present a 169% increased exposure to AcMPAG. Homozygosity for UGT1A7 387G/391A (129Lys/131Lys) is associated with a modest but significant 7% reduction in MPA level. When these additional genetic factors are considered in the model, the effects of previously described UGT1A9 and UGT2B7 variations remain significant. No significant effect is observed for UGT1A1*28, UGT1A7 622T/C (Trp208Arg), UGT1A9 -440TC/-331CT, UGT1A9 -118 TA(9/10) and seven other ABCC2 SNPs.


CONCLUSIONS
We demonstrate that MPA disposition is a multigenic process, and that additional studies are required to ascertain the relationship between UGT, ABCC2 genotypes and MPA pharmacokinetics in transplant recipients.
Lévesque
Eric
E
Laboratory of Pharmacogenomics, Oncology & Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, T3-48, 2705 Boul. Laurier, Québec, G1V 4G2, Canada.
Benoit-Biancamano
Marie-Odile
MO
Delage
Robert
R
Couture
Félix
F
Guillemette
Chantal
C
D000293:Adolescent; D000328:Adult; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D014018:Tissue Distribution; D000099148:UGT1A1 Enzyme
D020719:Glucuronides; D014453:Glucuronosyltransferase; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human; C524630:UGT1A7 protein, human