Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects

Abstract

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR–RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4 mg kg⁻¹). The plasma concentrations of cyclosporine were measured for up to 24 h post dose by high-performance liquid chromatography–electrospray mass spectrometry. We found that the mean C_max (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng ml⁻¹ (*18B/*18B) (p = 0.037) and the mean AUC0-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml-1 h (*18B/*18B) (p = 0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, T_max exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2 h post dose compared with *1/*18B (p = 0.062) or *1/*1 (p = 0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p > 0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.

Key Words::

• CYP3A4
• polymorphisms
• cyclosporine
• pharmacokinetics

Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (F 30130210 and 30371668), and by the China Medical Board of New York (grants 99-697 and 01-755). The authors thank Ms Yun-Peng Wu for her contribution in part to this project.