Preclinical pharmacokinetics and antitumor activity of imexon |
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Authors: | Robert T. Dorr James D. Liddil Mary Kay Klein Evan M. Hersh |
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Affiliation: | (1) Department of Pharmacology, Section of Hematology Oncology, Arizona Cancer Center, College of Medicine, 1515 N. Campbell Avenue, 85724 Tucson, Arizona;(2) Department of Internal Medicine, Section of Hematology Oncology, Arizona Cancer Center, College of Medicine, 1515 N. Campbell Avenue, 85724 Tucson, Arizona;(3) Clinical Lecturer, Hematology, Southwest Veterinary Oncology, 4131 E. Speedway, 85719 Tucson, Arizona, USA |
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Abstract: | Summary Imexon is an aziridine compound originally studied for immune-enhancing effects on lymphocytes. The drug was well-tolerated in humans and was shown to be active in a variety of animal tumor models. Recently, imexon has demonstrated antitumor activity in human multiple myeloma cell linesin vitro. The pharmacokinetics of the compound using a normal phase HPLC assay were studied in normal mice and in dogs with mast cell tumors. Doses of 100 mg/kg given intraperitoneally produced peak plasma levels over 100 ( ml in mice and the drug was rapidly eliminated with half lives of 8 minutes ( phase) and 29 minutes ( phase). Only 20% of an oral imexon dose was absorbed in the mouse. In dogs, the and phase half lives ranged from 18–26 minutes and 91–110 minutes, respectively. Peak levels over 100 g/ml were obtained following intravenous doses of 12.5 mg/kg and 25 mg/kg. Imexon was active in mice bearing either P-388 or L-1210 leukemia, but not in mice with B-16 melanoma. These results suggest that cytotoxic drug concentrations can be obtainedin vivo and that imexon is active in lymphoproliferative tumors. |
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Keywords: | Imexon pharmacokinetics aziridines leukemia |
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