Abstract

Penclomedine is a multi-chlorinated α-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 μM 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.