title: Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients.
abstract: 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.
authors: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors: Masatomo
authors: M
authors: Miura
authors: Shigeru
authors: S
authors: Satoh
authors: Kazuyuki
authors: K
authors: Inoue
authors: Hideaki
authors: H
authors: Kagaya
authors: Mitsuru
authors: M
authors: Saito
authors: Takamitsu
authors: T
authors: Inoue
authors: Toshio
authors: T
authors: Suzuki
authors: Tomonori
authors: T
authors: Habuchi
mesh_terms: 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*
chemical_list: 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