Patel D K, Woolley J L, Shcokcor J P, Johnson R L, Taylor L C, Sigel C W
Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Drug Metab Dispos. 1991 Mar-Apr;19(2):491-7.
Disposition and metabolism of crisnatol (14C-labeled), a novel antitumor agent, was examined after po and iv administration to rats. After both routes of drug administration, there was rapid elimination of the administered radioactivity in the urine (6-12% of the dose) and feces (81-92% of the dose). The drug appeared to be rapidly absorbed after oral dose and there was substantial "first-pass" metabolism. Analysis of the excreta indicated extensive metabolism of crisnatol by the rat, with the intact compound being the major radiolabeled component in the feces (17-20% of dose). Intact drug was not present in urine. Biotransformation of crisnatol by the rat mainly involves oxidation and conjugation pathways. Hydroxylation and dihydrodiol formation in the chrysene ring and oxidation of the propanediol side chain resulted in the formation of the three major fecal metabolites. The principal metabolite in the urine was also a dihydrodiol. Concentrations of intact drug in each tissue assayed exceeded those in plasma, and in the lungs the tissue/plasma ratio approached 300 and 82 at 2 hr after iv and po doses, respectively.
对新型抗肿瘤药物克瑞司那醇（14C标记）经口给药和静脉注射给大鼠后，对其处置和代谢情况进行了研究。两种给药途径后，尿液（剂量的6 - 12%）和粪便（剂量的81 - 92%）中给药的放射性均迅速消除。口服给药后药物似乎迅速吸收，且存在大量“首过”代谢。排泄物分析表明大鼠对克瑞司那醇进行了广泛代谢，完整化合物是粪便中主要的放射性标记成分（剂量的17 - 20%）。尿液中不存在完整药物。大鼠对克瑞司那醇的生物转化主要涉及氧化和结合途径。在屈环中形成羟基化和二氢二醇以及丙二醇侧链的氧化导致形成三种主要的粪便代谢物。尿液中的主要代谢物也是一种二氢二醇。所检测的每个组织中完整药物的浓度均超过血浆中的浓度，静脉注射和口服给药后2小时，肺组织/血浆比值分别接近300和82。
