Thompson K L, Chang M N, Chabala J C, Chiu S H, Eline D, Hucker H B, Sweeney B M, White S D, Arison B H, Smith J L
Department of Medicinal Chemical Research, Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065-0900.
Drug Metab Dispos. 1988 Sep-Oct;16(5):737-43.
The metabolism of the PAF antagonists kadsurenone and tritium-labeled 9,10-dihydrokadsurenone was studied in rhesus monkeys and rat liver microsomes. The monkey metabolites of the two drugs were isolated as their glucuronide conjugates from the urine of iv dosed males. The metabolites from both monkey and microsomal metabolism were purified by reverse phase HPLC and identified by spectral (NMR, UV, and mass spectrometric) analysis. The principal pathway of biotransformation of the tritium-labeled 9,10-dihydrokadsurenone in monkeys was hydroxylation of the C-5 propyl side chain to give two metabolites, 10-hydroxy-9,10-dihydrokadsurenone and 9-hydroxy-9,10-dihydrokadsurenone. These compounds were excreted as glucuronides. Microsomal incubation of tritium-labeled 9,10-dihydrokadsurenone yielded the 10-, 9-, and 8-hydroxy-9,10-dihydrokadsurenone as major metabolites. Kadsurenone was also metabolized at the C-5 side chain, an allyl group. The monoglucuronide of 9,10-dihydroxykadsurenone was isolated from monkey urine. Spectral analysis was not definitive as to the site of conjugation, and the structure of the metabolite was assigned as the C-10 conjugate. A major metabolite of rat liver microsomal incubation of kadsurenone was 9,10-dihydroxykadsurenone.
在恒河猴和大鼠肝微粒体中研究了血小板活化因子（PAF）拮抗剂海风藤酮和氚标记的9,10-二氢海风藤酮的代谢情况。通过静脉注射给药雄性恒河猴，从其尿液中分离出两种药物的猴代谢产物，它们均为葡糖醛酸共轭物。猴代谢产物和微粒体代谢产物均通过反相高效液相色谱法（HPLC）进行纯化，并通过光谱分析（核磁共振、紫外和质谱分析）进行鉴定。氚标记的9,10-二氢海风藤酮在猴体内的主要生物转化途径是C-5丙基侧链羟基化，生成两种代谢产物，即10-羟基-9,10-二氢海风藤酮和9-羟基-9,10-二氢海风藤酮。这些化合物以葡糖醛酸共轭物的形式排泄。氚标记的9,10-二氢海风藤酮在微粒体中孵育产生的主要代谢产物为10-、9-和8-羟基-9,10-二氢海风藤酮。海风藤酮在C-5侧链（烯丙基）处也会发生代谢。从猴尿中分离出了9,10-二羟基海风藤酮的单葡糖醛酸共轭物。光谱分析对于共轭位点并不明确，该代谢产物的结构被确定为C-10共轭物。海风藤酮在大鼠肝微粒体中孵育的主要代谢产物是9,10-二羟基海风藤酮。
