Penclomedine, a lipophilic alpha-
picoline derivative, is undergoing clinical development presently because of its pronounced antitumor activity against intracerebral (i.c.)
tumor xenografts.
Penclomedine may be metabolized in vivo to a more potent compound. Although it may be useful in the treatment of
brain tumors, the
drug has caused significant neurotoxicity in early clinical trials. The possibility that antitumor activity and neurotoxicity may be mediated by different mechanisms prompted a study assessing the differential distribution of
penclomedine and
penclomedine metabolites to brain and i.c.-implanted
tumors in rats. In the present study, quantitative autoradiographic analysis demonstrated a homogenous distribution of 14C-penclomedine in all organs within 1 h of administration. Levels of 14C-penclomedine in both i.c. and s.c.
tumors were three times higher than in normal brain tissue. High-performance liquid chromatography combined with gas chromatography and mass spectrophotometry demonstrated that two metabolites, O-demethyl
penclomedine and penclomic
acid, were responsible for most of the plasma radioactivity. Penclomic
acid was also the most common urinary metabolite of
penclomedine. In liver samples, although a large number of metabolite peaks were detected, no parent compound could be identified. However, in
tumors and all other tissues,
penclomedine was the main compound detected. The finding of
penclomedine in normal brain tissue indicates not only that this
drug may be useful in
tumors with normal blood-brain barrier function, but also that it may be directly neurotoxic.