他汀类药物血浆浓度的LC-MS/MS检测和利福平对他汀类药物药代动力学的影响
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摘要
过去的几十年里,临床药理学从一个小学科逐渐发展成为推动药理学进步的中坚力量,同时也成为生物医药研究中一个炙手可热的领域。临床药理学的研究发现药物血浆浓度受药物代谢酶和转运体的影响,药物效应除受到代谢酶和转运体影响之外,还受药物受体敏感性的影响。近年来,由于新药的广泛使用和联合用药的普遍性,药物间发生相互作用的机率也越来越大。深入研究药物相互作用及其机制,将有助于指导临床根据患者用药的具体情况来指导合理用药,调整药物的种类和剂量,以达到减少药物不良反应、确保药物治疗作用的目的。
有机阴离子转运多肽1B1(Organic anion transporting polypeptide1B1,OATP1B1,又称OATP-C,OATP2或LST1,编码基因为SLCO1B1)是一种特异性分布于肝细胞基底膜上的一种转运蛋白,与肝脏摄取多种内源性或外源性物质如胆红素、甲状腺激素、甲氨蝶呤、瑞格列奈和他汀类药物,如普伐他汀、瑞舒伐他汀、西伐他汀、匹伐他汀等密切相关,鉴于OATP1B1在介导生理功能和药物处置中的重要作用,对OATP1B1介导转运的药物之间相互作用的研究将有助于为临床合理用药提供指导。
本课题旨在查明利福平对OATP1B1底物瑞舒伐他汀和普伐他汀血浆药物浓度的影响及其临床意义。
本课题的主要研究结果如下:
1.通过复习文献,建立了液质联用法测定人血浆辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀和瑞舒伐他汀浓度,可简便、灵敏、准确用于测定血浆中这些药物的浓度并进行药物药代动力学研究。
2.建立液质联用法测定人血浆匹伐他汀浓度的方法,可简便、灵敏、准确用于测量血浆匹伐他汀浓度和生物等效性及药代动力学研究。
3.在中国健康小样本人群中,多剂量利福平不影响瑞舒伐他汀的药代动力学参数,这可能与利福平介导的CYP2C9诱导和OATP1B1抑制作用相互干扰有关。
4.在中国健康小样本人群中,单剂量口服600mg利福平可显著增加普伐他汀的药浓度。
总之,本项目建立了简便、灵敏、准确可测定人血浆辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀和匹伐他汀浓度的液质联用法,并在健康志愿者中研究了瑞舒伐他汀和普伐他汀与利福平的药物相互作用,可为临床合理使用该类药物提供参考。
In the past decades,clinical pharmacology has evolved from a minor discipline to a major driving force of pharmacology,and also became a sought-after biomedical research in the field.Clinical pharmacology studies indicate that plasma concentrations of drugs can be influenced by activities of drug-metabolizing enzymes and transporter.More and more novel medicines are emerged and combination drug therapy is commonly at present.Potential drug interactions should be awared when several drugs were coadministrated.Findings of clinical pharmacology study will guide us to choose the right drug and dosage to optimize drug therapy, avoid drug side effect,and obtain better therapeutic effects.
Organic anion transporting polypeptide 1B1(OATP1B1) is a sodium independent bile acid transporter,also known as liver-specific transporter 1(LST-1) or OATP-C,which is encoded by the gene SLCO1B1.It is specifically expressed at the basement membrane of human hepatocytes and is responsible for the hepatocellular uptake of a variety of endogenous and exogenous substrates such as bilirubin, thyroid hormone,methotrexate,repaglinide,pravastatin,rosuvastatin, cerivastatin and pitavastatin.Because of the important physiological and pharmacological function of OATP1B1,it will be helpful for the research of OATP1B1 mediated drug interaction.
Our present study was aimed to observe influence of rifampacin on the plasma concentration of OATP1B1 substrates,like rosuvastatin, pravastatin,and its clinical significance.
The major achievement of this project are as follows:
1.Comparison of previous literature to establish a LC-MS/MS method for determination of simvastatin,pravastatin,fluvastatin, atorvastatin and rosuvastatin in human plasma.This method is sensitive, simple and accurate that can be used for determination of the concentrations of statins in plasma as well as pharmacokinetics study of this group of drugs.
2.Established a LC-MS/MS method for determination of pitavastatin in human plasma.This method is sensitive,simple and accurate that can be used for determination of plasma concentration of pitavastatin and the pharmacokinetics study.
3.The pharmacokinetics parameters of rosuvastatin were not significantly changed by coadministration with multi-dose rifampicin in healthy small sample.The result might be explained by the opposing effects of rifampicin-mediated CYP2C9 induction and transporter-related inhibition on rosuvastatin.
4.We observed for the first time that coadministration of a single oral dose of rifampicin(600 mg) with pravastatin increases the plasma concentration of pravastatin in healthy volunteers.This obvious drug-drug interaction may result from inhibition of hepatic drug transporters by rifampicin,and thus decrease in biliary excretion of pravastatin.Therefore,when pravastatin is prescribed concomitantly with rifampicin,more attention should be paid to the toxicity of pravastatin.
In summary,we established sensitive,simple and accurate LC-MS/MS method for determination of pitavastatin in human plasma, and observed drug-drug interactions between rosuvastatin or pravastatin and rifampicin in healthy Chinese volunteers.This may provide some guidance for optimization of drug therapy.
有机阴离子转运多肽1B1(Organic anion transporting polypeptide1B1,OATP1B1,又称OATP-C,OATP2或LST1,编码基因为SLCO1B1)是一种特异性分布于肝细胞基底膜上的一种转运蛋白,与肝脏摄取多种内源性或外源性物质如胆红素、甲状腺激素、甲氨蝶呤、瑞格列奈和他汀类药物,如普伐他汀、瑞舒伐他汀、西伐他汀、匹伐他汀等密切相关,鉴于OATP1B1在介导生理功能和药物处置中的重要作用,对OATP1B1介导转运的药物之间相互作用的研究将有助于为临床合理用药提供指导。
本课题旨在查明利福平对OATP1B1底物瑞舒伐他汀和普伐他汀血浆药物浓度的影响及其临床意义。
本课题的主要研究结果如下:
1.通过复习文献,建立了液质联用法测定人血浆辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀和瑞舒伐他汀浓度,可简便、灵敏、准确用于测定血浆中这些药物的浓度并进行药物药代动力学研究。
2.建立液质联用法测定人血浆匹伐他汀浓度的方法,可简便、灵敏、准确用于测量血浆匹伐他汀浓度和生物等效性及药代动力学研究。
3.在中国健康小样本人群中,多剂量利福平不影响瑞舒伐他汀的药代动力学参数,这可能与利福平介导的CYP2C9诱导和OATP1B1抑制作用相互干扰有关。
4.在中国健康小样本人群中,单剂量口服600mg利福平可显著增加普伐他汀的药浓度。
总之,本项目建立了简便、灵敏、准确可测定人血浆辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀和匹伐他汀浓度的液质联用法,并在健康志愿者中研究了瑞舒伐他汀和普伐他汀与利福平的药物相互作用,可为临床合理使用该类药物提供参考。
In the past decades,clinical pharmacology has evolved from a minor discipline to a major driving force of pharmacology,and also became a sought-after biomedical research in the field.Clinical pharmacology studies indicate that plasma concentrations of drugs can be influenced by activities of drug-metabolizing enzymes and transporter.More and more novel medicines are emerged and combination drug therapy is commonly at present.Potential drug interactions should be awared when several drugs were coadministrated.Findings of clinical pharmacology study will guide us to choose the right drug and dosage to optimize drug therapy, avoid drug side effect,and obtain better therapeutic effects.
Organic anion transporting polypeptide 1B1(OATP1B1) is a sodium independent bile acid transporter,also known as liver-specific transporter 1(LST-1) or OATP-C,which is encoded by the gene SLCO1B1.It is specifically expressed at the basement membrane of human hepatocytes and is responsible for the hepatocellular uptake of a variety of endogenous and exogenous substrates such as bilirubin, thyroid hormone,methotrexate,repaglinide,pravastatin,rosuvastatin, cerivastatin and pitavastatin.Because of the important physiological and pharmacological function of OATP1B1,it will be helpful for the research of OATP1B1 mediated drug interaction.
Our present study was aimed to observe influence of rifampacin on the plasma concentration of OATP1B1 substrates,like rosuvastatin, pravastatin,and its clinical significance.
The major achievement of this project are as follows:
1.Comparison of previous literature to establish a LC-MS/MS method for determination of simvastatin,pravastatin,fluvastatin, atorvastatin and rosuvastatin in human plasma.This method is sensitive, simple and accurate that can be used for determination of the concentrations of statins in plasma as well as pharmacokinetics study of this group of drugs.
2.Established a LC-MS/MS method for determination of pitavastatin in human plasma.This method is sensitive,simple and accurate that can be used for determination of plasma concentration of pitavastatin and the pharmacokinetics study.
3.The pharmacokinetics parameters of rosuvastatin were not significantly changed by coadministration with multi-dose rifampicin in healthy small sample.The result might be explained by the opposing effects of rifampicin-mediated CYP2C9 induction and transporter-related inhibition on rosuvastatin.
4.We observed for the first time that coadministration of a single oral dose of rifampicin(600 mg) with pravastatin increases the plasma concentration of pravastatin in healthy volunteers.This obvious drug-drug interaction may result from inhibition of hepatic drug transporters by rifampicin,and thus decrease in biliary excretion of pravastatin.Therefore,when pravastatin is prescribed concomitantly with rifampicin,more attention should be paid to the toxicity of pravastatin.
In summary,we established sensitive,simple and accurate LC-MS/MS method for determination of pitavastatin in human plasma, and observed drug-drug interactions between rosuvastatin or pravastatin and rifampicin in healthy Chinese volunteers.This may provide some guidance for optimization of drug therapy.
引文
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