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Toxicity, Elimination, and Metabolism of 10-Ethyl-10-deazaaminopterin in Rats and Dogs¹

Clinical Pharmacology Laboratory [M. P. F., J. J. K., C. H., F. F., C. W. Y.], Laboratory for Molecular Therapeutics [L. L. S., F. M. S.], Pharmacology Laboratory [M. P. F., T-C. C., P. M. V.], Pathology Department [S. S. S.], and Biostatistics Laboratory [D. N.], Memorial Sloan-Kettering Cancer Center, New York, NY 10021, and Stanford Research Institute, Menlo Park, California 94025-3493 [J. I. D.]

10-Ethyl-10-deazaaminopterin (10-EdAM) is an antifolate compound with greater therapeutic activity than methotrexate against transplanted tumors in mice. When given weekly for 3 weeks, the 10% lethal dose in rats was 125 mg/kg (i.p.) and in dogs it was 2.5 mg/kg (i.v.). The major histopathological findings in intoxicated animals were damage to the mucosa of the gastrointestinal tract in rats and dogs and hypocellularity of the marrow in rats. The elimination of 50 mg/kg of 10-EdAM from the plasma of rats was triexponential with a terminal phase t of 18.5 h but a mean residence time of 0.7 h. The primary route of elimination in rats was biliary secretion of parent compound and eventual excretion of the parent compound and the deglutamate metabolite in the feces; the 7-hydroxy metabolite was also present in plasma, bile, and feces. Biliary elimination was independent of dose over a 5-fold range. The elimination of 10-EdAM from the plasma of dogs was also triexponential with a mean terminal phase t of 9.1 h and a mean residence time of 2.5 h; nonrenal clearance was the primary route of elimination. The pharmacokinetic parameters were independent of dose over the range of 0.25 to 5.0 mg/kg. High tissue concentrations of 10-EdAM were observed initially in liver, kidney, and small intestine of rats, while concentrations in bone marrow were low. Some polyglutamate formation was observed in these tissues as early as 0.5 h after drug administration but declined over 72 h.

¹ Supported in part by Public Health Service Grants CA-05826, CA-18856, CA-22764, and CA-08748 from the National Cancer Institute, NIH, Department of Health and Human Services, and a fellowship grant from the J. M. Foundation to M. P. F.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, Cornell University School of Medicine, 1275 York Ave., New York, NY 10021.

Received 6/25/86. Revised 1/20/87. Accepted 1/27/87.