Association of CYP3A4*18B and CYP3A5*3 polymorphisms with the pharmacokinetics of cyclosporine in Ch

来源 :2013年福建省医院药学年会 | 被引量 : 0次 | 上传用户:www_acafa_com
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  Background—Cyclosporine is a substrate of cytochrome P450 3A (CYP3A),some of the single nucleotide polymorphisms (SNPs) in these genes are associated with interindividual variations in cyclosporine pharmacokinetics.We studied the influence of these SNPs on cyclosporine pharmacokinetic parameters among healthy subjects.Methods—Fifty-six healthy Chinese subjects enrolled in the study received an oral dose of 5mg·kg-1 of cyclosporine after providing written informed consent.CYP3A5*3 and CYP3A4*18B was genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).The blood concentrations of cyclosporine were measured for up to 30 h after the dose by high-performance liquid chromatography.Results—The frequencies of CYP3A4*18B and CYP3A5*3 allele were 32.39% and 78.48%,respectively.The mean cyclosporine AUC0→30 and AUC0→∞ in the male group was significantly higher than in the female,the CL/F was significantly lower than in the female.The mean Cmax and AUC0→30 of cyclosporine for the CYP3A4*1/*1 (n=22)genotype groups were 1863.94 ± 325.70 μg·L-1 and 8510.26 ± 1865.70μg·h·L-1,which were much higher than the CYP3A4*1/*18B (n=23)genotype groups of 1666.47 ± 253.75 μg·L-1 and 8049.58±1483.41 μg·h·L-1,and the CYP3A4*18B/*18B (n=11)genotype groups of 1571.92 ± 372.71 μg·L-1 and 6866.44 ±1791.87 μg·h·L-1 (p<0.05,respectively).The CL/F of cyclosporine in the CYP3A4*18B/*18B group was significantly higher than that in the CYP3A4*1/*1 group and CYP3A4*1/*18B group (p=0.020).The mean Cmax and AUC0→30 of cyclosporine for the CYP3A5*1/*1 genotype groups were 1486.04±297.12 μg·L-1 and 3411.60±840.16 μg·h·L-1,which were significantly lower than the CYP3A5*3/*3 genotype groups of 1864.86±278.711 μg·L-1 (p=0.001) and 4208.09±797.86 μg·h·L-1 (p=0.014).The mean cyclosporine AUC0→30 and AUC0→∞ for the CYP3A4*18B/*18B group in CYP3A5 expressers (CYP3A5*1/*1 or *1/*3 genotype) were 6537.95±1499.55 μg·h·L-1 and 7526.11±1450.08 μg·h·L-1,which were much lower than the CYP3A4*1/*1 group of 8397.36±719.59 μg·h·L-1 and 9300.74 ± 1064.86 μg·h·L-1 (p < 0.05,respectively).The CL/F for the CYP3A4*18B/*18B group in CYP3A5 expressers was much higher than that in CYP3A4*1/*1 group (p=0.041).We did not observe any significant differences in cyclosporine pharmacokinetics among the three CYP3A4*18B groups in CYP3A5 nonexpressers.The mean Cmax for the CYP3A5*1/*1(*3) genotype groups were significantly lower than the CYP3A5*3/*3 genotype groups in CYP3A4*1/*1 carriers There were no statistical differences in cyclosporine pharmacokinetics among different CYP3A5*3 genotypes in CYP3A4*18B carriers.Conclusions—The current results indicate that gender and CYP3A4*18B,CYP3A5*3 genotypes could significantly effect cyclosporine pharmacokinetics in healthy Chinese subjects.
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