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European Journal of Clinical Pharmacology

, Volume 63, Issue 12, pp 1161–1169 | Cite as

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

  • Masatomo Miura
  • Shigeru SatohEmail author
  • Kazuyuki Inoue
  • Hideaki Kagaya
  • Mitsuru Saito
  • Takamitsu Inoue
  • Toshio Suzuki
  • Tomonori Habuchi
Pharmacokinetics and Disposition

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 AUC6–12 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.

Keywords

Mycophenolic acid Organic anion-transporting polypeptide SLCO1B3 T334G polymorphism ABCC2 Renal transplantation 

Notes

Acknowledgments

This work was partly supported by a grant (No.18923015) from the Japan Society for the Promotion of Science, Tokyo, Japan, and Novartis Ciclosporin Pharmaco-Clinical Forum Research Grant 2007, Tokyo, Japan.

Duality of interest

The authors declare that they have no conflict of interest related to the publication of this manuscript.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Masatomo Miura
    • 1
  • Shigeru Satoh
    • 2
    Email author
  • Kazuyuki Inoue
    • 1
  • Hideaki Kagaya
    • 1
  • Mitsuru Saito
    • 2
  • Takamitsu Inoue
    • 2
  • Toshio Suzuki
    • 1
  • Tomonori Habuchi
    • 2
  1. 1.Department of PharmacyAkita University HospitalAkitaJapan
  2. 2.Department of UrologyAkita University School of MedicineAkitaJapan

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