Influence of the CYP3A5 and MDR1 genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects

What is already known about this subject center dot It was found that the genetic polymorphisms of CYP3A5, CYP3A4 and MDR1 could affect the pharmacokinetics of tacrolimus. center dot This study was conducted to find such a possibility in the Korean population. What this study adds center dot CYP3A5 polymorphisms are likely to be associated with altered pharmacokinetics of tacrolimus in Koreans. center dot MDR1 polymorphisms have no important role in the pharmacokinetics of tacrolimus. To determine the frequencies of the genotypes of CYP3A5 and MDR1 and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population. Twenty-nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for CYP3A4*1B, CYP3A5*3, MDR1 c.1236C -> T, MDR1 c.2677G -> A/T and MDR1 c.3435C -> T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined. No subject in this study had the CYP3A4*1B variant. The observed frequencies of CYP3A5*1/*1, *1/*3, and *3/*3 were 0.069 [confidence interval (CI) -0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC(0-infinity) for the CYP3A5*1/*1 or *1/*3 genotype was 131.5 +/- 44.8 ng h ml(-1) (CI 109.6, 153.5), which was much lower compared with the CYP3A5*3/*3 genotype of 323.8 +/- 129.3 ng h ml(-1) (CI 253.5, 394.1) (P = 2.063E-07). Similarly, C-max for the CYP3A5*1/*1 or *1/*3 genotype was 11.8 +/- 3.4 ng ml(-1) (CI 10.1, 13.5), which was also much lower compared with the CYP3A5*3/*3 genotype of 24.4 +/- 12.3 ng ml(-1) (CI 17.8, 31.1) (P = 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the MDR1 diplotypes of CGC-CGC, CGC-TTT, CGC-TGC, TTT-TGC or TTT-TTT (P = 0.2486). This study shows that the CYP3A5*3 genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.