高血脂患者中氟伐他汀群体药代动力学特征的研究  

Population pharmacokinetic study of fluvastatin in patients with hyperlipemia

作　　者：刘志军[1] 张红[1] 熊玉卿[1] 

机构地区：[1]南昌大学临床药理研究所江西省临床药物代谢动力学重点实验室,南昌330006

出　　处：《中国临床药理学杂志》2017年第13期1207-1211,共5页The Chinese Journal of Clinical Pharmacology

基　　金：国家自然科学基金资助项目(81260508)

摘　　要：目的用非线性混合效应模型(NONMEM)建立氟伐他汀在高血脂患者群体药代动力学(PPK)模型,并探讨影响PPK特征的相关因素。方法以52例原发性高血脂患者为研究对象,患者服用氟伐他汀40,80 mg后,用HPLC-MS/MS法检测氟伐他汀血药浓度,用限制性片段长度多态性(RFLP-PCR)法检测OATP1B1基因多态性;用NONMEM建立氟伐他汀PPK模型,考察一般生物学特征和基因多态性和实验室生化指标等45个变量对药代动力学参数的影响,用自举法进行验证。结果氟伐他汀在高脂血症患者体内的PPK可用一房室模型描述,个体间变异符合乘法模型。氟伐他汀的清除率和分布容积的群体典型值分别为1.16×10^(-1)L·h^(-1)和4.16×10~3L。有机阴离子转运多肽1B1(OATP1B1)388A>G、OATP1B1 521T>C、合并丹参制剂给药、年龄对氟伐他汀的PPK参数有显著影响。模型计算值和500次自举法验证值相符。结论 OATP1B1 388位点突变降低清除率,合并丹参制剂给药升高清除率,OATP1B1 521位点突变降低分布容积,分布容积随年龄增大而增大。本研究建立的氟伐他汀PPK模型稳定可靠。Objective To build up population pharmacokinetics（ PPK）model of fluvastatin in patients with hyperlipidemic Using nonlinear mixed effect model（ NONMEM）,thus discussing the relevant factors that could influence the population pharmacokinetics characteristics. Methods Fifty-two cases of primary hyperlipidemic patients were given 40 mg or 80 mg fluvastatin orally and plasma concentrations of fluvastatin were determined by HPLC-MS/MS,organic anion transporting polypeptide 1B1（ OATP1B1） gene polymorphism was checked by method of RFLP-PCR. The PPK model of fluvastatin was established with NONMEM,effects of 45 variables on pharmacokinetics parameters,such as general biological characteristics,genetic polymorphism and laboratory biochemical parameters,were investigated and verified by bootstrap procedure.Results The pharmacokinetics of simvastatin in patients with hyperlipidemia can be described by a one compartment model,and the inter-individual variation was consistent with the multiplicative model. Typical values of clearance and volume of distribution were 1. 16 × 10^（-1）L·h^（-1）and 4. 16 × 10~3 L. The PPK parameters were significantly influenced by OATP1B1 388 A G,521 T C,OATP1B1,combination with Danshenagent and age of fluvastatin. The parameters from Bootstrap didn＇ t appear to be much difference from NONMEM.Conclusion Clearance of fluvastatin was reduced by OATP1B1 388 site mutations and raised by combining with Danshan agent,volume of distribution was lowered by OATP1B1 521 site mutation,increased with age and the older,the greater of the distribution volume. In this study,the establishment of the model of population pharmacokinetics of fluvastatin was stable and reliable,which provided a basis for the rational use of fluvastatin.

关 键 词：氟伐他汀 高血脂患者 群体药代动力学 

分 类 号：R972.6[医药卫生—药品]