Keywords: Liquid Chromatography Tandem Mass Spectrometry, Simvastatin, Human plasma

IntrOductIOn Simvastatin is cholesterol-lowering drug which competitively inhibits the cholesterol biosynthesis by HMG-CoA reductase [1]. Simvastatin is chemically modified 2,2-dimethyll butyrate analogue of lovastatin [2]. Simvastatin is orally administered as inactive prodrug in the lactone form which is converted in the liver into its active metabolite β-hydroxy acid [3]. Recently, numerous methods for analysis of simvastatin and its metabolites determination in human plasma by HPLC methods with difference detectors (ultraviolet, fluorescence and mass spectrometry) have been published [4-9]. In addition, some methods of gas chromatography with mass spectrometry for determination of simvastatin and its metabolites have also been published [10-11]. However, most of these methods are tedious and time consuming, which also considered costly for routine analysis work. Method by HPLC-UV is not sensitive enough to detect the low concentration of simvastatin and can only detect as low as 20 ng/mL of simvastatin. Since plasma concentrations of simvastatin is expected to be between 0.1 and 15 ng/mL [12]. However, method by HPLC-UV is suitable for determining simvastatin in pharmaceutical formulations and preparations [13], but is not suitable for pharmacokinetic study. Therefore, sensitive and selective methods for the determination of simvastatin are required for therapeutic drug level monitoring. A more sensitive method using LC/MS/MS, can be achieved, but the operation and clean up procedure prior to analysis seems to be so complicated and is too expensive to be used for routine measurements in the clinical laboratory [6,8,9]. Electrospray ionization mass spectrometry (ESI-MS) coupled with LC-MS method developed by Yang et al., (2003) was simple, rapid and sensitive. In this study, develop more sensitive and specific liquid chromatography tandem mass spectrometric (LC-MS-MS) method which can simultaneously quantitate simvastatin in human plasma to the required level. Also in this study, sample sizes 0.2 mL was used to achieve the desired limit of quantification at 0.25 ng/mL of simvastatin in human plasma. P ha rm ac o lo g y S ec tio n