Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients.
Mycophenolic acid (MPA) is mainly glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the phenolic MPA glucuronide (MPAG). MPAG is excreted by transporters such as organic anion-transporting polypeptide (gene SLCO), multidrug resistance protein 2 (gene ABCC2), breast cancer resistance protein (BCRP, gene ABCG2) or P-glycoprotein (gene ABCB1). This study investigated the association of UGTs, SLCOs, ABCB1, ABCC2, and ABCG2 polymorphisms with MPAG pharmacokinetics in 80 Japanese renal transplant recipients. Eighty recipients were given repeated doses of combination immunosuppressive therapy consisting of mycophenolate mofetil and tacrolimus every 12 hours at a designated time (0900 and 2100). On day 28, after renal transplantation, plasma concentrations of MPA and MPAG were measured by high-performance liquid chromatography. There were no significant differences in the area under the plasma concentration-time curve (AUC) ratio of MPAG/MPA between UGT1A1, UGT1A6, UGT1A7, UGT1A8, and UGT1A9 I399C/T genotypes. On the other hand, the median dose-adjusted AUC0-12 of MPAG in SLCO1B1 1a/1a+1a/1b+1b+1b (n = 53) and 1a/*15 + 1b/*15+*15/*15 (n = 27) were 1549 and 1134 mg.h L g, respectively (P = 0.03004 in multivariate analysis). The median dose-adjusted AUC0-12 of MPAG in SLCO1B3 334T/T+T/G (699G/G+G/A, n = 46) and 334G/G (699A/A, n = 34) was 1191 and 1580 mg.h L g, respectively (P = 0.02792 in multivariate analysis). There were no significant differences in the dose-adjusted AUC0-12 of MPAG between the ABCB1 C3435T and ABCC2 C-24T genotypes. However, the dose-adjusted AUC0-12 of MPAG was significantly lower in recipients with ABCG2 421C/A+A/A (n = 44) than in those with C/C (n = 36) (P = 0.0295). In conclusion, our findings showed that MPAG pharmacokinetics were significantly influenced by SLCO1B1 and SLCO1B3 polymorphisms and not by UGT polymorphisms. BCRP rather than multidrug resistance protein 2 seems to be the transporter associated with biliary excretion of MPAG.
Miura
Masatomo
M
Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, Japan. mmiura@hos.akita-u.ac.jp
Kagaya
Hideaki
H
Satoh
Shigeru
S
Inoue
Kazuyuki
K
Saito
Mitsuru
M
Habuchi
Tomonori
T
Suzuki
Toshio
T
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D020719:Glucuronides / Q000097:blood / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000097:blood / Q000235:genetics*; D006801:Humans; D016030:Kidney Transplantation; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009363:Neoplasm Proteins / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D014180:Transplantation / Q000502:physiology*; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D020719:Glucuronides; D014453:Glucuronosyltransferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D009363:Neoplasm Proteins; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C000715591:UGT1A9 protein, human; C113145:mycophenolic acid glucuronide; C110655:UDP-glucuronosyltransferase, UGT1A6; C454320:UDP-glucuronosyltransferase, UGT1A8; C524630:UGT1A7 protein, human