Ahmed Tamer A, Horn Jamie, Hayslip John, Leggas Markos
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Avenue, Lexington, Kentucky 40536-0596, USA.
Markey Cancer Center, University of Kentucky, 800 Rose Street, Lexington, Kentucky 40536-0293, USA.
J Pharm Anal. 2012 Dec;2(6):403-411. doi: 10.1016/j.jpha.2012.07.010. Epub 2012 Aug 7.
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.
辛伐他汀（SIM）是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，广泛用于高脂血症治疗。最近，人们对高于高脂血症治疗剂量的辛伐他汀的抗癌活性进行了研究。这促使我们研究高剂量辛伐他汀在癌症患者中的药代动力学。为此，开发了一种液相色谱-串联质谱（LC-MS/MS）方法，用于测量从患者获得的血浆和外周血单核细胞（PBMC）中的辛伐他汀及其酸形式（SIMA）。使用75:25（% v/v）乙腈：醋酸铵（0.1 M，pH 5.0）流动相在反相柱上进行色谱分析物分离。在配备涡轮离子喷雾源并以正离子模式运行的三重四极杆质谱仪上进行检测。该测定法在血浆中辛伐他汀的线性范围为2.5-500 ng/mL，SIMA为5-500 ng/mL；在细胞裂解物中辛伐他汀的线性范围为2.5-250 ng/mL，SIMA为5-250 ng/mL。血浆和细胞裂解物中辛伐他汀的回收率>58%，SIMA的回收率>75%。辛伐他汀和SIMA在血浆、细胞裂解物和重构溶液中均稳定。该方法成功应用于高剂量辛伐他汀在癌症患者药代动力学研究中收集的血浆和PBMC样本中辛伐他汀和SIMA的测定。
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