MURINE AND HUMAN IN-VIVO PENCLOMEDINE METABOLISM

Penclomedine is a multichlorinated alpha picoline derivative which has shown prominent activity in murine breast cancer models and is curren tly undergoing clinical development, Previous in vitro research has id entified several penclomedine metabolites. In this study, human and mu rine in vivo penclomedine metabolism was examined, Upon i.v. administr ation to mice, no penclomedine was detectable in plasma at time points as early as 1 h postinfusion, The principle metabolite was demethyl-p enclomedine -2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine]. Both pe nclomedine 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 metabolit es of penclomedine consisted mainly of penclomic acid and additional p olar metabolites, The results obtained after p.o. administration were nearly identical to i.v. administration with respect to the extent, le vel, and type of metabolites found in the plasma, tissues, and urine a nd with respect to the extent of protein binding, In human subjects ad ministered penclomedine daily for 5 consecutive days, demethyl-penclom edine could be detected in plasma and accumulated with successive dose s of penclomedine, reaching peak plasma concentrations of up to 10 tim es that of penclomedine itself and plasma exposures of nearly 400 time s that of the parent drug, It appears that patients eliminate penclome dine largely through metabolism and that this drug may be amenable to p.o. administration.