Penclomedine is a multi-chlorinated alpha-picoline derivative that has demonstrated activity in several murine breast cancer models and is currently in clinical testing for use against solid tumors. This study evaluates the metabolism of penclomedine in several in vitro hepatic models, including microsomes, fresh liver slices, and the isolated perfused rat liver (IPRL). Both human and mouse liver slices as well as human and mouse liver microsomes under aerobic conditions resulted in limited metabolism of penclomedine to several oxidized metabolites, including penclomic acid, 4-demethylpenclomic acid, and 4-demethylpenclomedine. Microsomes under anaerobic conditions vigorously produced mainly reduced metabolites, primarily penclomedine dimers. This is in contrast to in vivo data, which showed rapid metabolism of penclomedine to primarily 4-demethylpenclomedine. The IPRL preparation, however, metabolized 50 microM penclomedine 90% within 90 min, producing primarily 4-demethylpenclomedine and penclomic acid. These were formed in roughly equimolar amounts and did not undergo significant further metabolism over 4 hr. Numerous highly polar biliary metabolites were also found. The IPRL preparation thus seems to most accurately reflect the in vivo situation.
Download full-text PDF |
Source |
|---|
Publication Analysis
Top Keywords
Similar Publications
Intestinal absorption of penclomedine from lipid vehicles in the conscious rat: contribution of emulsification versus digestibility.
Int J Pharm
February 2004
Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, P.O. Box 177, 31080, Pamplona, Spain.
While the inclusion of highly lipophilic compounds in self-emulsifying drug delivery systems (SEDDS) is often reported to result in strongly enhanced oral absorption, it is still controversial whether further lipolysis of the dispersed lipidic material is required for final transfer to the enterocyte membranes. In order to assess the relative roles of lipid vehicle dispersion and vehicle digestibility in the oral absorption of penclomedine (Pcm), a series of formulations of Pcm in medium chain triglyceride (MCT)/tocophersolan (TPGS) was developed having three sizes (160 nm, 720 nm, and mm-sized ('crude' oil)); with or without the inclusion of tetrahydrolipstatin (THL), a known lipase-inhibitor. Oral absorption of Pcm was studied after administration of small volumes of these formulations in the conscious rat.
View Article and Find Full Text PDFThe alkylating agent penclomedine induces degeneration of purkinje cells in the rat cerebellum.
Invest New Drugs
August 2003
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Purpose: Penclomedine (PEN), a multichlorinated alpha-picoline derivative which is metabolized to highly reactive alkylating species, was selected for clinical development due to its prominent activity against a wide range of human tumor xenografts when administered either parentally or orally. Its principal dose-limiting toxicity in preclinical and clinical studies has been neurocerebellar toxicity, which has been related to the magnitude of peak plasma PEN concentrations, but not to plasma concentrations of its putative principal alkylating metabolite, 4,o-demethylpenclomedine (DMPEN). These observation, as well as PEN's toxicologic, pharmacologic, and tissue distribution profiles, have suggested that the parent compound is primarily responsible for cerebellar toxicity.
View Article and Find Full Text PDFPhase I clinical and pharmacokinetic study of oral penclomedine (NSC 338720) in adults with advanced solid malignancy.
Clin Cancer Res
March 2002
University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792, USA.
Penclomedine is a synthetic alpha-picoline derivative that has shown antitumor activity both in preclinical development and in Phase I work using an i.v. preparation.
View Article and Find Full Text PDFBioavailability of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine.
Cancer Chemother Pharmacol
September 2001
The Johns Hopkins Oncology Center, Baltimore, MD 21287-8934, USA.
Purpose: Oral administration of penclomedine was investigated based on preclinical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (Cmax) of the neurotoxic parent species.
View Article and Find Full Text PDFAcyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine.
Cancer Chemother Pharmacol
July 2001
Southern Research Institute, Birmingham, AL 35255-5305, USA.
Purpose: The purpose of this investigation was to compare the antitumor activities of a series of acyl derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) observed to be an active antitumor agent in vivo and non-neurotoxic in a rat model with that of DM-PEN.
Methods: Acyl derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted subcutaneously (s.c.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!