Impact of the CYP3A4*1G Polymorphism and its Combination with CYP3A5 Genotypes on Tacrolimus Pharmacokinetics in Renal Transplant Patients

Abstract

Aim: Tacrolimus is a substrate of CYP3A4 and CYP3A5. The present study investigated the impact of the CYP3A4*1/*1G polymorphism compared with CYP3A5 genotypes on the dose-adjusted pharmacokinetics of tacrolimus. The effects of the polymorphism on the variability in tacrolimus pharmacokinetics among patients with the CYP3A5*1 allele (CYP3A5 expresser) and among those with CYP3A5*3/*3 genotype (nonexpresser) were also studied. Materials & methods: A total of 136 renal allograft recipients were given repeated doses of tacrolimus every 12 h. On day 28 after the renal transplantation, blood tacrolimus concentrations were measured, and dose-adjusted pharmacokinetics were determined and compared with the corresponding genotype. Results: The dose-adjusted AUC_0–12 and C₀ of tacrolimus were significantly lower in patients with the CYP3A4*1G allele and CYP3A5 expressers than those with the CYP3A4*1/*1 genotype and nonexpressers, respectively. In a multiple regression analysis, the dose-adjusted AUC_0–12 and C₀ values were associated with CYP3A4*1/*1 (p = 0.018 and 0.040, respectively) and CYP3A5*3/*3 (p < 0.001 each). The standardized regression coefficient for the AUC_0–12 of tacrolimus was approximately twofold less for CYP3A4*1/*1 than CYP3A5*3/*3. The lowest dose-adjusted AUC_0–12 was found in CYP3A5 expressers with the CYP3A4*1G allele. Conclusion: The CYP3A4*1/*1G polymorphism was associated with the pharmacokinetics of tacrolimus, however, its contribution to dose-adjusted pharmacokinetics was approximately twofold less than that of the CYP3A5*1/*3 polymorphism. Although its effect on CYP3A4 activity is not clear, CYP3A4*1/*1G may be a candidate for a polymorphism affecting the interindividual variability in tacrolimus pharmacokinetics among CYP3A5 expressers.

Original submitted 5 January 2011; Revision submitted 22 February 2011

KEYWORDS::

• CYP3A4
• CYP3A5
• pharmacogenomics
• polymorphism
• tacrolimus

Financial & competing interests disclosure

This work was supported by grants from the Japan Society (No.20591894 and No.18923015) for the Promotion of Science, Tokyo, Japan, and the Japan Research Foundation for Clinical Pharmacology, Tokyo, Japan, and the Research Foundation for Pharmaceutical Sciences, Tokyo, Japan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by grants from the Japan Society (No.20591894 and No.18923015) for the Promotion of Science, Tokyo, Japan, and the Japan Research Foundation for Clinical Pharmacology, Tokyo, Japan, and the Research Foundation for Pharmaceutical Sciences, Tokyo, Japan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.