Xiang Q, Li C, Zhao X, Cui Y M
Department of Pharmacy, Base for Clinical Trial, Peking University First Hospital, Beijing, China.
J Clin Pharm Ther. 2017 Jun;42(3):345-349. doi: 10.1111/jcpt.12505. Epub 2017 Feb 28.
The role of CYP3A5 in drug metabolism has been receiving attention because CYP3A5 may be more involved in the metabolism of CYP3A substrates in vivo than previously thought. The polymorphism of transporters, such as P-gp (P-glycoprotein) and breast cancer-related protein (BCRP), influences the metabolism of these substrates, and felodipine is a substrate of P-gp. The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodipine in healthy Chinese subjects.
A single dose of 5 mg felodipine was orally administered to 45 healthy Chinese subjects. The serum concentration of felodipine was measured by using LC/MS/MS. We detected the SNPs of cytochromes P450 enzymes and transporters, which play vital roles in drug metabolism and have a high frequency of mutation in Chinese population.
The area under the plasma concentration-time curve (AUC) within the time points 0 to 72 h (AUC ) after felodipine administration was significantly higher in subjects possessing the BCRP421AA alleles than in those with the BCRP421 CC or CA genotype (P = 0·034). The subjects with CYP3A5*3/3 (n = 27) had higher felodipine exposure than CYP3A51/*3 (n = 15) (P = 0·035).
This study showed that the genetic polymorphisms of CYP3A5*3 and BCRPC421A might explain the variability in the pharmacokinetics of felodipine in the Chinese population.
CYP3A5在药物代谢中的作用一直备受关注，因为CYP3A5在体内可能比之前认为的更多地参与CYP3A底物的代谢。转运蛋白的多态性，如P-糖蛋白（P-gp）和乳腺癌相关蛋白（BCRP），会影响这些底物的代谢，而非洛地平是P-gp的底物。本研究的目的是评估健康中国受试者中非洛地平处置的药物遗传学变异性。
对45名健康中国受试者口服单剂量5mg非洛地平。采用液相色谱-质谱联用（LC/MS/MS）法测定非洛地平的血清浓度。我们检测了细胞色素P450酶和转运蛋白的单核苷酸多态性（SNP），这些在药物代谢中起重要作用且在中国人群中具有高突变频率。
非洛地平给药后0至72小时（AUC）内的血浆浓度-时间曲线下面积（AUC），在携带BCRP421AA等位基因的受试者中显著高于携带BCRP421 CC或CA基因型的受试者（P = 0·034）。携带CYP3A5*3/3（n = 27）的受试者比携带CYP3A51/*3（n = 15）的受试者有更高的非洛地平暴露量（P = 0·035）。
本研究表明，CYP3A5*3和BCRPC421A的基因多态性可能解释中国人群中非洛地平药代动力学的变异性。
