Pharmacology and toxicity of a potent "nonclassical" 2,4-diamino quinazoline folate antagonist, trimetrexate, in normal dogs.
The pharmacology of trimetrexate (JB-11, NSC 249008, 2,4-diamino-5-methyl-5-[(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 microM and were equal to or greater than 0.1 microM at 1 and 24 hr, respectively. The predominant pharmacokinetics of trimetrexate plasma disappearance was an elimination phase with a t1/2 of 3.5 hr. Concentrations in the cerebrospinal 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 microM) for therapeutic effects.
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005243:Feces / Q000032:analysis; D005493:Folic Acid Antagonists; D006207:Half-Life; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000378:metabolism*; D012016:Reference Values; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014018:Tissue Distribution; D016597:Trimetrexate
D005493:Folic Acid Antagonists; D011799:Quinazolines; D013762:Tetrahydrofolate Dehydrogenase; D016597:Trimetrexate