Association Between Tacrolimus Pharmacokinetics and Cytochrome P450 3A5 and Multidrug Resistance Protein 1 Exon 21 Polymorphisms.

Abstract

BACKGROUND Individual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single-nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. METHODS Thirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction-restriction fragment length polymorphism analysis. TAC concentrations were determined 3 weeks after renal transplantation and PK parameters calculated. RESULTS The area under the blood concentration-time curve (AUC) in CYP3A5 expressers was significantly higher than that in CYP3A5 nonexpressers (CYP3A5*3/*3). Patients with the MDR1 exon 21 A allele (G2677A) showed higher dose-adjusted AUC (AUC/D) and lower doses of TAC than those who did not possess that allele. Furthermore, patients with both CYP3A5*3/*3 and MDR1 G2677A showed significantly lower TAC doses and higher dose-adjusted trough levels (C/D) and AUC/D than those without those genotypes. There was no significant association between MDR1 exon 26 polymorphism and the PK of TAC. CONCLUSIONS Patients with both CYP3A5*3/*3 and MDR1 G2677A had higher blood TAC concentrations than those without those genotypes. Japanese patients should be carefully monitored for consideration of lower TAC doses, because 24% of Japanese patients have double mutations.

DOI: 10.1016/j.transproceed.2017.03.093

Cite this paper

@article{Soda2017AssociationBT, title={Association Between Tacrolimus Pharmacokinetics and Cytochrome P450 3A5 and Multidrug Resistance Protein 1 Exon 21 Polymorphisms.}, author={Mitsuhiro Soda and Mikihiro Fujitani and R Michiuchi and Author Shibayama and Kengo Kanamori and Satoshi Yoshikuni and Y Ohno and T Tsuchiya and Alfredo Takashi Suzuki and Kouji Horie and Takashi Deguchi and Yoshito Itoh and Kiyoyuki Kitaichi}, journal={Transplantation proceedings}, year={2017}, volume={49 6}, pages={1492-1498} }