Khetarpal V K, Storbeck L S, Wells D, Meacham R H
Preclinical Drug Disposition Department, Rhone-Poulenc Rorer Central Research, Horsham, PA 19044.
J Chromatogr. 1991 Jul 5;567(2):491-7. doi: 10.1016/0378-4347(91)80157-8.
The new drug RG 12561 (I) is a lactone that is undergoing clinical evaluation for its cholesterol lowering effect based on potent HMG CoA reductase inhibitory activity displayed by its open hydroxy acid form. To determine the dispositional characteristics of the drug, a method was developed for determination of the two forms in plasma. A 0.25-ml aliquot of plasma was deproteinized with 0.5 ml of methanol, and the lactone was extracted with hexane-ethyl acetate (75:25, v/v). The methanolic plasma was then acidified followed by extraction of the hydroxy acid with hexane-ethyl acetate. The extracts were dried, reconstituted and analyzed by isocratic, reversed-phase high-performance liquid chromatography using ultraviolet absorbance at 254 nm. The separations were performed utilizing a C18 column with mobile phase consisting of acetonitrile, 2-propanol and 0.1 M acetate buffer (pH 5), the proportions of which differed depending on the form of drug analyzed. The method was found to be selective and a quantitation limit of 50 ng/ml was established. Validation studies demonstrated that the method was sufficiently accurate and precise for determining disposition of the drug in the dog.
新药RG 12561（I）是一种内酯，因其开环羟酸形式具有强大的HMG CoA还原酶抑制活性，正在进行降胆固醇作用的临床评估。为了确定该药物的处置特征，开发了一种测定血浆中两种形式的方法。取0.25 ml血浆等分试样，加入0.5 ml甲醇进行脱蛋白处理，然后用己烷 - 乙酸乙酯（75:25，v/v）萃取内酯。接着将甲醇化血浆酸化，再用己烷 - 乙酸乙酯萃取羟酸。提取物干燥后复溶，并通过等度反相高效液相色谱法在254 nm处进行紫外吸光度分析。分离使用C18柱进行，流动相由乙腈、2 - 丙醇和0.1 M乙酸盐缓冲液（pH 5）组成，其比例根据分析的药物形式而有所不同。该方法具有选择性，定量限为50 ng/ml。验证研究表明，该方法对于确定药物在犬体内的处置足够准确和精密。
