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.