TISSUE AND TUMOR DISTRIBUTION OF C-14 PENCLOMEDINE IN RATS

Penclomedine, a lipophilic cy-picoline derivative, is undergoing clini cal development presently because of its pronounced antitumor activity against intracerebral (i.c.) tumor xenografts. Penclomedine may be me tabolized in vivo to a more potent compound. Although it may be useful in the treatment of brain tumors, the drug has caused significant neu rotoxicity in early clinical trials. The possibility that antitumor ac tivity and neurotoxicity may be mediated by different mechanisms promp ted a study assessing the differential distribution of penclomedine an d penclomedine metabolites to brain and i.c.-implanted tumors in rats. In the present study, quantitative autoradiographic analysis demonstr ated a homogenous distribution of C-14-penclomedine in all organs with in 1 h of administration. Levels of C-14-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 an d mass spectrophotometry demonstrated that two metabolites, O-demethyl penclomedine and penclomic acid, were responsible for most of the pla sma radioactivity. Penclomic acid was also the most common urinary met abolite 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 neuroto xic.