Validated LC-MS/MS method for simultaneous determination of SIM and its acid form in human plasma and cell lysate: Pharmacokinetic application  

作　　者：Tamer A. Ahmed Jamie Horn John Hayslip Markos Leggas 

机构地区：[1]Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky [2]Markey Cancer Center, University of Kentucky

出　　处：《Journal of Pharmaceutical Analysis》2012年第6期403-411,共9页药物分析学报（英文版）

摘　　要：Simvastatin （SIM） is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC-MS/MS method was developed to measure SIM and its acid form （SIMA） in plasma and peripheral blood mononuclear cells （PBMCs） obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75：25 （% v/v） acetonitrile：ammonium acetate （0.1 M, pH 5.0） mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5-500 ng/mL for SIM and 5-500 ng/mL for SIMA in plasma and 2.5-250 ng/mL for SIM and 5-250 ng/mL for SIMA in cell lysate. Recovery was 〉 58% for SIM and 〉 75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients.Simvastatin （SIM） is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used in hyperlipidemia therapy. SIM has recently been studied for its anticancer activity at doses higher than those used for the hyperlipidemia therapy. This prompted us to study the pharmacokinetics of high-dose SIM in cancer patients. For this purpose, an LC-MS/MS method was developed to measure SIM and its acid form （SIMA） in plasma and peripheral blood mononuclear cells （PBMCs） obtained from patients. Chromatographic analyte separation was carried out on a reverse-phase column using 75：25 （% v/v） acetonitrile：ammonium acetate （0.1 M, pH 5.0） mobile phase. Detection was performed on a triple quadrupole mass spectrometer, equipped with a turbo ion spray source and operated in positive ionization mode. The assay was linear over a range 2.5-500 ng/mL for SIM and 5-500 ng/mL for SIMA in plasma and 2.5-250 ng/mL for SIM and 5-250 ng/mL for SIMA in cell lysate. Recovery was 〉 58% for SIM and 〉 75% for SIMA in both plasma and cell lysate. SIM and SIMA were stable in plasma, cell lysate and the reconstitution solution. This method was successfully applied for the determination of SIM and SIMA in plasma and PBMCs samples collected in the pharmacokinetic study of high-dose SIM in cancer patients.

关 键 词：SIMVASTATIN LC-MS/MS Human plasma Cell lysate PHARMACOKINETIC HIGH-DOSE 

分 类 号：R96[医药卫生—药理学]