Zhao Ying, Zhai Desheng, He Hui, Li Tingting, Chen Xijing, Ji Hui
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Eur J Clin Pharmacol. 2009 Jun;65(6):579-84. doi: 10.1007/s00228-009-0619-6. Epub 2009 Feb 11.
Our objective was to study the effects of polymorphic the CYP3A5 (allele *1 and *3), MDR1 [single nucleotide polymorphisms (SNPs) G2677T, C3435T] and CACNA1C (SNPs rs2239128, rs2239050, rs2238032) genes on nimodipine oral disposition and response in healthy Chinese subjects.
Pharmacokinetics and pharmacodynamics data were obtained from a bioequivalence study, and the same 20 subjects were genotyped for CYP3A, MDR1 and CACNA1C. An additional 41 healthy Chinese subjects were recruited to obtain an indication of the distribution of CACNA1C polymorphisms in the Chinese population. Racial differences in the frequency of CACNA1C alleles were assessed. The phenotype differences between genotypes were analyzed.
The allelic frequencies of rs2239050 and rs2238032 in our Chinese cohort were different from those in a Caucasian population (p < 0.01). Subjects with mutant alleles (*3/*3) of the CYP3A5 gene had a decreased oral clearance of nimodipine, with a higher lnC(max) or 1n AUC(0-infinity) compared with those subjects with the heterozygote (*1/*3) or wild type (*1/*1) gene. The CACNA1C rs2239128 C and rs2239050 G SNPs were associated with a stronger efficacy compared with their respective alleles, rs2239128 T and rs2239050 C. MDR1 polymorphisms showed no significance in terms of nimodipine disposition.
The polymorphic CYP3A5 (allele *1 and *3) and CACNA1C genes have effects on nimodipine oral disposition and response in healthy Chinese subjects. The homozygous variant of CYP3A5 (*3/*3) was associated with significantly increased nimodipine exposure. CACNA1C SNPs rs2239128 C and rs2239050 G were associated with a stronger efficacy.
我们的目标是研究CYP3A5基因多态性（等位基因1和3）、MDR1基因[单核苷酸多态性（SNP）G2677T、C3435T]以及CACNA1C基因（SNP rs2239128、rs2239050、rs2238032）对健康中国受试者尼莫地平口服处置及反应的影响。
从一项生物等效性研究中获取药代动力学和药效学数据，对同一20名受试者进行CYP3A、MDR1和CACNA1C基因分型。另外招募41名健康中国受试者，以了解CACNA1C基因多态性在中国人群中的分布情况。评估CACNA1C等位基因频率的种族差异。分析不同基因型之间的表型差异。
我们中国队列中rs2239050和rs2238032的等位基因频率与白种人群不同（p < 0.01）。携带CYP3A5基因纯合突变等位基因（*3/*3）的受试者尼莫地平口服清除率降低，与携带杂合子（*1/*3）或野生型（*1/*1）基因的受试者相比，其lnC(max)或1n AUC(0-∞)更高。与各自的等位基因rs2239128 T和rs2239050 C相比，CACNA1C rs2239128 C和rs2239050 G单核苷酸多态性与更强的疗效相关。MDR1基因多态性在尼莫地平处置方面无显著意义。
CYP3A5基因多态性（等位基因1和3）以及CACNA1C基因对健康中国受试者尼莫地平口服处置及反应有影响。CYP3A5的纯合变异体（*3/*3）与尼莫地平暴露显著增加相关。CACNA1C单核苷酸多态性rs2239128 C和rs2239050 G与更强的疗效相关。
