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  • Title: Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis.
    Author: Shi XJ, Geng F, Jiao Z, Cui XY, Qiu XY, Zhong MK.
    Journal: J Clin Pharm Ther; 2011 Oct; 36(5):614-24. PubMed ID: 21916909.
    Abstract:
    WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (TAC) is metabolized mainly by the CYP3A subfamily and extruded into the intestine by P-glycoprotein, which is encoded by the ABCB1 gene. Several studies have suggested that the CYP3A5*3 genotype influenced the pharmacokinetics (PK) of TAC. The CYP3A4*18B and CYP3A5*3 alleles are clinically important in Chinese subjects because of their relatively high frequency. The present study aimed at evaluating the effects of ABCB1 (C1236T-G2677T/A-C3435T), CYP3A4*18B and CYP3A5*3 genetic polymorphisms on TAC PK in healthy Chinese subjects. METHODS: Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC-MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed-effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs. RESULTS AND DISCUSSION: Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the TAC PK, whereas ABCB1 genetic polymorphisms and other demographic characteristics did not. The combined genotypes of CYP3A4*18B and CYP3A5*3 had a greater impact than either genotype alone, and they were estimated to account for 28·4% of the inter-subject variability of apparent clearance (CL/F) by NONMEM. The CL/F in subjects with CYP3A4*1/*1-CYP3A5*3/*3 was 10·3 L/h and was 48·5% in those not carrying CYP3A4*1/*1-CYP3A5*3/*3. WHAT IS NEW AND CONCLUSION: This is the first study to extensively explore the influence of CYP3A4*18B, CYP3A5*3 and ABCB1 genetic polymorphisms on TAC PK in healthy Chinese subjects. The results demonstrated that subjects with a combined genotype of CYP3A4*1/*1-CYP3A5*3/*3 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.
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