Impact of CYP3A5 and MDR1(ABCB1) C3435T Polymorphisms on the Pharmacokinetics of Tacrolimus in Renal Transplant Recipients

• DOI: 10.1016/j.transproceed.2005.02.073
• Publication Date: 2005-05-25T11:44:44Z
• Authors: H. Tada; N. Tsuchiya; S. Satoh; H. Kagaya; Z. Li; K. Sato; M. Miura; T. Suzuki; T. Kato; T. Habuchi
• Keywords: Genotype; Genetic Carrier Screening; Kidney Transplantation; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Tacrolimus; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Cytochrome P-450 Enzyme System; Area Under Curve; Cytochrome P-450 CYP3A; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Immunosuppressive Agents; Polymorphism, Restriction Fragment Length

The objective of this study was to assess the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Japanese renal transplant recipients.The pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation. Polymerase chain reaction-restriction fragment length polymorphism and direct sequence methods were used for CYP3A5 and MDR1 polymorphisms, respectively.The dose-adjusted area under the concentration-time curve (AUC0-12) was significantly lower among CYP3A5*1 carriers than those bearing CYP3A5*3/*3. (0.570 +/- 0.105 vs 0.865 +/- 0.343 ng.h/mL per mg/kg, P = .00322). The daily tacrolimus dose per body weight was significantly higher in CYP3A5*1 carriers than those of CYP3A5*3/*3 carriers (0.271 +/- 0.110 vs 0.150 +/- 0.056 mg/kg, P = .00016). In this study, a distinction was made between carriers of CYP3A5*1/*1+*1/*3 and CYP3A5*3/*3 to investigate the influence of the MDR1 C3435T mutation on tacrolimus pharmacokinetics. The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group.Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC0-12 of tacrolimus. In contrast, MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.