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.