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

• Published in: European journal of clinical pharmacology 2007-12, Vol.63 (12), p.1161-1169
• Main Authors: MIURA, Masatomo, SATOH, Shigeru, INOUE, Kazuyuki, KAGAYA, Hideaki, SAITO, Mitsuru, INOUE, Takamitsu, SUZUKI, Toshio, HABUCHI, Tomonori
• Format: Article
• Language: English
• Subjects: Adult; Antibiotics, Antineoplastic - blood; Antibiotics, Antineoplastic - pharmacokinetics; Area Under Curve; Biological and medical sciences; Drug therapy; Female; Genes; Genotype; Humans; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Japan; Kidney Transplantation; Kidneys; Male; Medical sciences; 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; Pharmacology; Pharmacology. Drug treatments; Polymorphism; Polymorphism, Genetic; Solute Carrier Organic Anion Transporter Family Member 1b1; Solute Carrier Organic Anion Transporter Family Member 1B3; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Transplants & implants
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-007-0380-7

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. 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. 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). 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.