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GW23-e0855
EFFECT OF AMLODIPINE ON THE PHARMACOKINETICS OF TACROLIMUS IN RELATION TO CYP3A5*3 GENETIC POLYMORPHISM IN HEALTHY CHINESE SUBJECTS
  1. Zuo XC1,
  2. Zhang BK1,
  3. Li J2,
  4. Cheng ZN2,
  5. Liu Z2,
  6. Yang GP1,
  7. Tan HY1,
  8. Tang SH1,
  9. Pei Q1,
  10. Zhou LY1,
  11. Yuan H1
  1. 1Clinical Pharmacy and Pharmacology Research department, Third Xiangya Hospital, Central South University
  2. 2School of Pharmaceutical Sciences, Central South University

    Abstract

    Objectives To investigate the effect of amlodipine on the pharmacokinetics of tacrolimus in relation to CYP3A5*3 genetic polymorphism in healthy Chinese subjects.

    Methods 1. A PCR-RFLP technique was used for CYP3A5*3 genotyping.

    2. HPLC-MS/MS methods were applied to determine the tacrolimus whole blood samples.

    3. An open, randomised, three-period crossover clinical trial was used to investigate the effect of amlodipine on the pharmacokinetics of tacrolimus in healthy volunteers in relation to different CYP3A5*3 genotypes.

    Results 1. The oral clearance of tacrolimus in CYP3A5*1/*1 or CYP3A5*1/*3 group was significantly higher than that in CYP3A5*3/*3, the area under the concentration (AUC) of tacrolimus was less than that in the latter.

    2. When tacrolimus and amlodipine were coadministrated with single dose or multiple dose in CYP3A5*1/*1 or CYP3A5*1/*3 subjects, the AUC of tacrolimus in coadministration group was significantly higher than that in tacrolimus alone group.

    3. For CYP3A5*3/*3 subjects, the AUC of tacrolimus in tacrolimus plus amlodipine group is significantly lower than that in tacrolimus alone group when the two drugs are administrated with multiple-dose, while there was no significant difference in the AUC of tacrolimus between them when the two drugs are administrated with single-dose.

    Conclusions 1. CYP3A5*3 is an important factor affecting the tacrolimus pharmacokinetics.

    2. Among the CYP3A5*1/*1 and CYP3A5*1/*3 subjects, amlodipine raises significantly the whole blood tacrolimus concentration.

    3. Among the CYP3A5*3/*3 subjects, amlodipine raises the oral clearance of tacrolimus and decrease the blood tacrolimus concentration.

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