Patel D K, Lewis R P, Hinton M L, Schroeder D H, Shockcor J P, Johnson R L, Sigel C W
Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Drug Metab Dispos. 1993 Jan-Feb;21(1):62-70.
The pharmacokinetics, metabolism, and qualitative tissue distribution of 502U83, a compound with antineoplastic activity, were examined in the rat. After an oral dose, average maximum plasma concentrations of 5.3 micrograms/ml were achieved at 0.28 hr, indicating rapid absorption of the compound; the bioavailability was estimated to be 62%. After intravenous administration the half-life was 1.73 hr. Autoradiographs of rats dosed intravenously with [14C]502U83 showed the presence of significant levels of radioactivity in the bone marrow, salivary gland, thymus, and lung; highest levels were in the gastrointestinal tract. There was no evidence of penetration of radioactivity into the brain. After an intravenous administration of [14C]502U83, a mean of 94.1% of the dose was recovered in 72 hr, with 46.6% in the urine and 47.5% in the feces. HPLC analysis of the radiocarbon in urine and feces revealed the presence of at least six common radioactive peaks, each representing approximately 2 to 12% of the dose. Biotransformation of 502U83 by the rat mainly involves oxidation of the hydroxyethyl group, and one or both of the hydroxymethyl groups leading to three major metabolites, common to urine and feces. Parent drug was the major component in both urine and feces, respectively, accounting for 18% and 10% of the dose in 48 hr. The glucuronic acid conjugate of the parent drug was a minor metabolite (< 2% of the dose). There was no evidence of metabolism on the anthracene ring.
对具有抗肿瘤活性的化合物502U83在大鼠体内的药代动力学、代谢及定性组织分布进行了研究。口服给药后，在0.28小时达到平均最大血浆浓度5.3微克/毫升，表明该化合物吸收迅速；生物利用度估计为62%。静脉给药后的半衰期为1.73小时。用[14C]502U83静脉给药的大鼠的放射自显影片显示，骨髓、唾液腺、胸腺和肺中有显著水平的放射性；胃肠道中的放射性水平最高。没有证据表明放射性穿透进入大脑。静脉注射[14C]502U83后，72小时内平均回收了94.1%的剂量，其中46.6%在尿液中，47.5%在粪便中。对尿液和粪便中的放射性碳进行HPLC分析，发现至少有六个常见的放射性峰，每个峰约占剂量的2%至12%。大鼠对502U83的生物转化主要涉及羟乙基的氧化，以及一个或两个羟甲基的氧化，产生三种主要代谢产物，尿液和粪便中都有。母体药物分别是尿液和粪便中的主要成分，在48小时内分别占剂量的18%和10%。母体药物的葡萄糖醛酸结合物是次要代谢产物（<剂量的2%）。没有证据表明蒽环发生代谢。
