Hartman N R, Leo K U, Brewer T G, Strong J M
Laboratory of Clinical Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD 20708, USA.
Drug Metab Dispos. 1998 Jun;26(6):513-9.
Penclomedine is a multi-chlorinated alpha-picoline derivative that has demonstrated activity in several murine breast cancer models and is currently in clinical testing for use against solid tumors. This study evaluates the metabolism of penclomedine in several in vitro hepatic models, including microsomes, fresh liver slices, and the isolated perfused rat liver (IPRL). Both human and mouse liver slices as well as human and mouse liver microsomes under aerobic conditions resulted in limited metabolism of penclomedine to several oxidized metabolites, including penclomic acid, 4-demethylpenclomic acid, and 4-demethylpenclomedine. Microsomes under anaerobic conditions vigorously produced mainly reduced metabolites, primarily penclomedine dimers. This is in contrast to in vivo data, which showed rapid metabolism of penclomedine to primarily 4-demethylpenclomedine. The IPRL preparation, however, metabolized 50 microM penclomedine 90% within 90 min, producing primarily 4-demethylpenclomedine and penclomic acid. These were formed in roughly equimolar amounts and did not undergo significant further metabolism over 4 hr. Numerous highly polar biliary metabolites were also found. The IPRL preparation thus seems to most accurately reflect the in vivo situation.
喷氯米定是一种多氯代α-甲基吡啶衍生物，已在多种小鼠乳腺癌模型中显示出活性，目前正处于针对实体瘤的临床试验阶段。本研究评估了喷氯米定在几种体外肝脏模型中的代谢情况，包括微粒体、新鲜肝切片和离体灌注大鼠肝脏（IPRL）。在有氧条件下，人及小鼠肝切片以及人及小鼠肝微粒体对喷氯米定的代谢有限，生成了几种氧化代谢产物，包括喷氯米酸、4-去甲基喷氯米酸和4-去甲基喷氯米定。在厌氧条件下，微粒体主要大量生成还原代谢产物，主要是喷氯米定二聚体。这与体内数据相反，体内数据显示喷氯米定迅速代谢为主要的4-去甲基喷氯米定。然而，IPRL制剂在90分钟内将50微摩尔的喷氯米定代谢了90%，主要生成4-去甲基喷氯米定和喷氯米酸。它们以大致等摩尔量形成，在4小时内未发生显著的进一步代谢。还发现了许多高极性的胆汁代谢产物。因此，IPRL制剂似乎最准确地反映了体内情况。
