Division of Clinical Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
Chirality. 2011 Aug;23(7):495-503. doi: 10.1002/chir.20932. Epub 2011 Jun 10.
Itraconazole is an antifungal drug widely used in a variety of fungal infections, which have become a significant public-health problem in recent decades. Itraconazole is a chiral drug consisting of two diastereoisomeric racemates, i.e., four stereoisomers. Data in the literature suggests that stereochemistry may play a significant role in the action and disposition of the drug and therefore stereoselective analytical methods for the determination of the drug in biological fluids are needed for the elucidation of that role. We report a stereoselective HPLC method that incorporates solvent extraction, the use of an internal standard, two chiral stationary phases in series, and fluorescence detection. The procedure is enantioselective and partially diastereoselective and provides the concentrations in blood plasma of the two epimer mixtures 2R,4S,2'R/2R,4S2'S and 2S,4R,2'R/2S,4R,2'S, respectively, each of which is a combination of the two epimers that differ in the configuration at the sec-butyl group. The analytical method has suitable sensitivity, recovery, precision, and accuracy. Analysis of the plasma of a human subject six hours after the oral administration of a single 200-mg dose of itraconazole showed a 3.4-fold difference between the concentrations of the epimer mixtures. The method has certain advantages over the published alternative procedure that uses LC-MS.
伊曲康唑是一种广泛应用于各种真菌感染的抗真菌药物，近年来已成为一个重大的公共卫生问题。伊曲康唑是一种手性药物，由两种非对映异构体的外消旋体组成，即四种立体异构体。文献中的数据表明，立体化学可能在药物的作用和分布中发挥重要作用，因此需要立体选择性分析方法来测定生物体液中的药物，以阐明其作用。我们报告了一种立体选择性 HPLC 方法，该方法结合了溶剂萃取、内标、串联使用两个手性固定相和荧光检测。该方法具有对映选择性和部分非对映选择性，可分别提供两种差向异构体混合物 2R,4S,2'R/2R,4S2'S 和 2S,4R,2'R/2S,4R,2'S 在血浆中的浓度，每个混合物都是在仲丁基构型上存在差异的两种差向异构体的组合。分析方法具有合适的灵敏度、回收率、精密度和准确性。对人类受试者口服单剂量 200 毫克伊曲康唑 6 小时后的血浆进行分析，结果显示差向异构体混合物的浓度相差 3.4 倍。该方法与使用 LC-MS 的已发表替代方法相比具有某些优势。
