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.