Tissue and tumor distribution of C-penclomedine in rats

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...

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Bibliographic Details
Published in:Clinical cancer research 1996-03, Vol.2 (3), p.541
Main Authors: O'Reilly, S, Hartman, N R, Grossman, S A, Strong, J M, Struck, R F, Eller, S, Lesser, G J, Donehower, R C, Rowinsky, E K
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacokinetics
Autoradiography
Brain - metabolism
Carbon Radioisotopes
Kidney - metabolism
Liver - metabolism
Male
Neoplasms, Experimental - metabolism
Picolines - pharmacokinetics
Rats
Rats, Sprague-Dawley
Tissue Distribution
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Summary: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.
ISSN:1078-0432
1557-3265