LC-MS/MS Method Determine The Concentration Of Statins And Effect Of Rifampicin On The Pharmacokinetics Of Statins

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.