SLCO1B1 genetic polymorphism influences mycophenolic acid tolerance in renal transplant recipients

Pharmacogenomics. 2010 Dec;11(12):1703-13. doi: 10.2217/pgs.10.132.

Abstract

Aims: This study aimed to determine the influence of gene candidates on mycophenolic acid (MPA) response during the first year of renal transplantation.

Materials & methods: A total of 218 renal transplant recipients who received MPA from the first day of transplantation at a fixed dose of 2 g/day were genotyped for ABCB1, ABCC2, UGT2B7, UGT1A9, SLCO1B1, SLCO1B3 and IMPDH1 polymorphisms. Clinical end points were MPA-related adverse drug reactions (ADRs) and acute rejection episodes during the first year post-transplantation.

Results: After correction for multiple statistical testing, SLCO1B1 (encoding the hepatic uptake transporter OATP1B1) was the only gene associated with MPA-related ADRs, showing a 75% risk reduction in favor of a protective effect of the SLCO1B1*5 allele (p = 0.002). In vitro experiments showed that MPA metabolites MPA-phenyl-glucuronide and MPA-acyl-glucuronide are substrates of OATP1B1. Their transport was decreased in the presence of the variant transporter (OATP1B1*5).

Conclusion: These results suggest for the first time that carriers of the SLCO1B1*5 allele seem to be protected from MPA-related ADRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biotransformation / genetics
  • Cell Line
  • DNA / genetics
  • Female
  • Graft Rejection / genetics*
  • Graft Rejection / prevention & control
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / therapeutic use
  • Kidney Transplantation*
  • Leukocytes / metabolism
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Middle Aged
  • Mycophenolic Acid / administration & dosage
  • Mycophenolic Acid / adverse effects
  • Mycophenolic Acid / analogs & derivatives*
  • Mycophenolic Acid / pharmacokinetics
  • Mycophenolic Acid / therapeutic use
  • Organic Anion Transporters / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide*
  • Retrospective Studies
  • Substrate Specificity
  • Transfection

Substances

  • Immunosuppressive Agents
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • SLCO1B1 protein, human
  • DNA
  • Mycophenolic Acid