The effects of polymorphism of cytochrome P450 CYP3A5 on the initial concentration of blood tacrolimus in recipients after renal transplantation

Abstract

Objective To investigate the role of polymorphism of cytochrome P450 CYP3A5 in determination of initial tacrolimus(Tac)dosages and the influence on trough concentrations in early period after renal transplantation．Methods All the cases received relative living renal transplantation de novo and immunosuppressive protocol was Tac+MMF+ prednisone．The study was conducted in 2 successive stages：in stage 1 (dosage-fixed group，n=28)，fixed tac initial dose 0．1 mg·kg~(-1)·d~(-1) was administered to the recipients regardless of CYP3A5 genotypes；in stage 2(dosage-adjusted group，n=40)，the adjusted Tac initial dosages based on CYP3A5 genotype for the expressers(only CYP3A5*1／*3 included，and those with CYP3A5*1／*1 were excluded)and non-expressers (CYP3A5*3／*3)were 0．15 mg·kg~(-1)·d~(-1) and 0．08 mg·kg~(-1)·d~(-1)，respectively．The blood samples were drawn from patients for Tac level measurement on the 3rd，5th，7th and 14th day post-operation，and concentration-to-adjusted dose ratio(C／D ratio)was used to indicate the tested drug level．Results In the dosage-fixed group，there were 15 cases carrying CYP3A5*1／*3 and 13 carrying CYP3A5 *3／*3．In the dosage-adjusted group，there were 16 cases carrying CYP3A5*1／*3 and 24 carrying CYP3A5*3／*3．In two groups，C／D ratio among recipients with CYP3A5*1／-16 3 was all markedly lower than that with CYP3A5*3／*3(both P<0．05)at different time points(Day 3，5，7，14)．46．7 0A(7／15)cases carrying CYP3A5*1／*3 and 46．2%(6／13)carrying*3／*3 achieved target blood tacrolimus concentration in the fixed-dosage group，while 81．2%(13／16)，and 75．0%(18／24) carrying CYP3A5*1／*3 and*3／*3 reached target concentration in the dosage-adjusted group，respectively．The percentages of different CYP3A5 genotype carriers reaching target concentration in the dosage-adjusted group were all markedly higher than those in the dosage-fixed group(P<O．05)．Conclusion Adiustment of Tac initial dose by CYP3A5 genotype is flexible and can facilitate achieving target concentration rapidly in early stage after renal transplantation Key words: CYP3A5; Genotype; Tacrolimus; Plasma concentration; Kidney transplantation