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Murine Pharmacokinetics and Metabolism of Penclomedine [3,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine, NSC 338720]¹

Mayo Clinic and Foundation, Department of Oncology, Division of Developmental Oncology Research, Rochester, Minnesota 55905

Penclomedine, a highly substituted pyridine derivative, has been selected by the National Cancer Institute for evaluation as a potential anticancer agent based on antitumor activity observed in murine tumor models following i.v., p.o., and i.p. administration. We have developed a reverse-phase high performance liquid chromatography assay for PEN, and subsequently investigated murine pharmacokinetics and metabolism. Following rapid i.v. injection of PEN (300 mg/m²) to mice, plasma elimination was best described by a 2-compartment open model with an elimination phase half-life, total body clearance, and steady-state distribution volume of 69 min, 114 ml/min/m², and 4800 ml/m², respectively. While PEN displayed good p.o. absorption, bioavailability of PEN after p.o. administration was approximately 2% of that observed following i.v. administration. Metabolism contributed substantially to drug clearance, and total metabolites were slowly eliminated from plasma. After i.v. and p.o. administration of radiolabeled PEN, <0.2% of the parent drug was excreted in the 48-h urine, and 25–30% of the total radioactivity was recovered in urine. NADPH-dependent oxidative and reductive metabolism was observed when penclomedine was incubated with mouse microsomal preparations. Microsomal reductive metabolism of PEN led to formation of a metabolite tentatively identified as a molecule formed by dimerization of the radical species produced by cleavage of chlorine from the trichloromethyl moiety of penclomedine.

¹ Supported in part by National Cancer Institute Contract CM-97618, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Mayo Clinic and Foundation, Department of Oncology, Division of Developmental Oncology Research, 200 First Street Southwest, Rochester, MN 55905.

Received 6/14/91. Accepted 3/10/92.

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