Association of ABCB1, CYP3A4*18B and CYP3A5*3 genotypes with the pharmacokinetics of tacrolimus in healthy Chinese subjects: a population pharmacokinetic analysis

作者：Shi X J; Geng F; Jiao Z^*; Cui X Y; Qiu X Y; Zhong M K

来源：Journal of Clinical Pharmacy and Therapeutics, 2011, 36(5): 614-624.

DOI：10.1111/j.1365-2710.2010.01206.x

• ABCB1
• CYP3A4*18B
• CYP3A5*3
• population pharmacokinetics
• tacrolimus

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*11-CYP3A5*33 was 10.3 L/h and was 48.5% in those not carrying CYP3A4*11CYP3A5*33.
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*11CYP3A5*33 may require lower TAC doses to achieve target concentration levels and further investigation is needed in larger populations to confirm the clinical benefits.

• 出版日期2011-10
• 单位复旦大学