Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients.
OBJECTIVE
We investigated the association between mycophenolic acid (MPA) pharmacokinetics and organic anion-transporting polypeptide (OATP/SLCO)1B1, 1B3, 2B1 and multidrug resistance-association protein 2 (MRP2/ABCC2) genetic polymorphisms and diarrhea.


METHODS
Eighty-seven renal allograft recipients were given repeated doses of mycophenolate mofetil every 12 h at a designated time (09:00 and 21:00). The pharmacokinetics of MPA were analyzed on day 28 posttransplantation.


RESULTS
The dose-adjusted area under the cuve (AUC)(6-12) of MPA, an estimate of enterohepatic recirculation, was greater in SLCO1B3 T334G GG (or G699A AA) carriers than in TT carriers (or G699A GG) (40 vs. 25 ng h/mL per milligram, respectively, P = 0.0497). None of the polymorphism of SLCO1B1, SLCO2B1, or ABCC2 C-24T were associated with MPA pharmacokinetics or diarrhea. However, the oral clearance of MPA in recipients having both the SLCO1B3 T334G GG genotype and the ABCC2 C-24T T allele was significantly lower than in patients having both the SLCO1B3 T334G TT and ABCC2 C-24T CC genotypes (0.15 vs. 0.18 L/h per kilogram, respectively, P = 0.0010).


CONCLUSIONS
MPA excretion into bile in patients with SLCO1B3 T334G GG (or G699A AA) was higher than in those with T334G TT (or G699A GG), probably resulting in a higher AUC(6-12) value of MPA. MPA uptake into hepatocytes and excretion into bile at first pass may be greater in SLCO1B3 T334G GG carriers than in TT carriers. In addition, the ABCC2 C-24T polymorphism also seems to be associated with enhanced enterohepatic circulation of MPA. The SLCO1B3 and ABCC2 transporters rather than uridine diphosphate-glucuronosyltransferase (UGT) may partly affect interindividual variety in plasma MPA concentration.
Miura
Masatomo
M
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Satoh
Shigeru
S
Inoue
Kazuyuki
K
Kagaya
Hideaki
H
Saito
Mitsuru
M
Inoue
Takamitsu
T
Suzuki
Toshio
T
Habuchi
Tomonori
T
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007564:Japan; D016030:Kidney Transplantation; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009173:Mycophenolic Acid / Q000097:blood / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000235:genetics* / Q000494:pharmacology; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D011110:Polymorphism, Genetic; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D016559:Tacrolimus; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human