Penclomedine is a multichlorinated alpha-picoline derivative which has shown prominent activity in murine breast cancer models and is currently undergoing clinical development. Previous in vitro research has identified several penclomedine metabolites. In this study, human and murine in vivo penclomedine metabolism was examined. Upon i.v. administration to mice, no penclomedine was detectable in plasma at time points as early as 1 h postinfusion. The principle metabolite was demethyl-penclomedine [3, 5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine]. Both penclomedine and demethyl-penclomedine could be recovered from tissues. Greater than 60% of the penclomedine dose remaining in the body at 22 h was indelibly bound to tissue and plasma proteins. Urinary metabolites of penclomedine consisted mainly of penclomic acid and additional polar metabolites. The results obtained after p. o. administration were nearly identical to i.v. administration with respect to the extent, level, and type of metabolites found in the plasma, tissues, and urine and with respect to the extent of protein binding. In human subjects administered penclomedine daily for 5 consecutive days, demethyl-penclomedine could be detected in plasma and accumulated with successive doses of penclomedine, reaching peak plasma concentrations of up to 10 times that of penclomedine itself and plasma exposures of nearly 400 times that of the parent drug. It appears that patients eliminate penclomedine largely through metabolism and that this drug may be amenable to p.o. administration.

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