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Pharmacology and Toxicity of a Potent "Nonclassical" 2,4-Diamino Quinazoline Folate Antagonist, Trimetrexate, in Normal Dogs¹

Section of Comparative Medicine [E. C. W.], and Departments of Pharmacology and Medicine [A. R. C., R. N. D., M. L. G., N. H., B. A. M., W. L. S., J. R. B.], Yale University School of Medicine, New Haven, Connecticut 06510

The pharmacology of trimetrexate (JB-11, NSC 249008, 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline), an antitumor agent effective against several mouse tumors, was studied in normal dogs. A high-performance liquid chromatographic technique with electrochemical detection, dihydrofolate reductase inhibition assay, and ¹⁴C-labeled drug were used to measure plasma disappearance, tissue distribution, excretion, and metabolism of the drug at doses from 0.5 to 6 mg/kg. Doses of 2 mg/kg were well tolerated without toxicity. Higher doses (3 to 6 mg/kg) produced mainly intestinal toxicity without significant hematological or liver abnormalities. The 6-mg/kg dose caused severe bloody diarrhea.

After administration of 3 mg/kg, plasma concentrations of trimetrexate were 1 µM and were equal to or greater than 0.1 µM at 1 and 24 hr, respectively. The predominant pharmaco-kinetics of trimetrexate plasma disappearance was an elimination phase with a t of 3.5 hr. Concentrations in the cere-brospinal fluid were 2 to 5% of that in plasma and were maximum within 1 to 2 hr after i.v. administration. Highest tissue concentrations of drug were measured in liver and kidney; lowest were found in brain and lung. A dose equivalent to 3 mg/kg in humans (on a sq m basis) should produce adequate plasma concentrations (greater than 0.1 µM) for therapeutic effects.

¹ Supported by USPHS Grants CA 08010 and CA 16359.

² Present address: 6 Friary Road, Wraysbury, Staines, Middlesex, England.

³ American Cancer Society Professor. To whom requests for reprints should be addressed.

Received 7/27/81. Accepted 1/29/82.

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