title: 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 mgkg(-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 AUCO-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.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Y F
authors.initials: YF
authors.lastname: Hu
authors.forename: J H
authors.initials: JH
authors.lastname: Tu
authors.forename: Z R
authors.initials: ZR
authors.lastname: Tan
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: J
authors.initials: J
authors.lastname: He
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: H H
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D016572:Cyclosporine / Q000378:metabolism / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human