Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects |
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| Authors: | Y.-F. Hu J.-H. Tu Z.-R. Tan Z.-Q. Liu Professor G. Zhou J. He |
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| Affiliation: | 1. Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, People's Republic of China;2. Peking University Third Hospital, Beijing, People's Republic of China;3. Peking University Third Hospital, Beijing, People's Republic of China |
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| 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 Cmax (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, Tmax 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. |
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| Keywords: | CYP3A4 polymorphisms cyclosporine pharmacokinetics |
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