Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients

Eur J Clin Pharmacol. 2007 Dec;63(12):1161-9. doi: 10.1007/s00228-007-0380-7. Epub 2007 Sep 29.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibiotics, Antineoplastic / blood
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Area Under Curve
  • Female
  • Genotype
  • Humans
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics*
  • Japan
  • Kidney Transplantation*
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics
  • Mycophenolic Acid / blood
  • Mycophenolic Acid / pharmacokinetics*
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / pharmacology
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Polymorphism, Genetic*
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Tacrolimus / blood
  • Tacrolimus / pharmacokinetics*

Substances

  • Antibiotics, Antineoplastic
  • Immunosuppressive Agents
  • Liver-Specific Organic Anion Transporter 1
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • SLCO2B1 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • multidrug resistance-associated protein 2
  • Mycophenolic Acid
  • Tacrolimus