Metabolic disposition of trimetrexate, a nonclassical dihydrofolate reductase inhibitor, in rat and dog.
The metabolic disposition of trimetrexate, a nonclassical inhibitor of dihydrofolate reductase, was characterized in the rat. After iv administration of 1.2 mg/kg [14C]trimetrexate (as the glucuronate), recovery of total radioactivity in urine and feces through 144 hr was greater than 96% of dose. Trimetrexate was extensively metabolized, with only 13% of the dose excreted unchanged in urine and bile. Profiling of biliary and urinary radioactivity showed three components and unchanged drug accounted for the majority of excreted radioactivity (75% of dose). Tandem mass spectral analysis of one urinary component suggested trimetrexate had undergone N-dealkylation and oxidation to 2,4-diamino-5-methyl-6-quinazolinecarboxylic acid. Structural assignment for this metabolite was confirmed by comparison to authentic reference material. Mass spectral analysis of a second component gave a quasimolecular ion (MH)+ at m/z 532 with a key fragment ion at m/z 356 (MH-176)+, characteristic of a glucuronide conjugate. The proton NMR spectrum of this component was consistent with expectations for a glucuronide conjugate of 4'-O-desmethyl trimetrexate. Possible formation of a sulfate conjugate was explored by co-administration of unlabeled trimetrexate with [35S]sulfate to rats. A 35S-labeled component was excreted in urine, which co-eluted with the third major urinary 14C-labeled component observed in the first experiment. Mass spectrum of this component was consistent with the structure of trimetrexate-4'-O-desmethyl sulfate. In dogs, the disposition of trimetrexate was examined using stable isotope-labeled material. The dose was 10 mg/kg administered iv as a 1:1 mixture of 13C2, 15N-labeled and unlabeled trimetrexate glucuronate.(ABSTRACT TRUNCATED AT 250 WORDS)
Wong
B K
BK
Pharmacokinetics/Drug Metabolism Department, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company.
Woolf
T F
TF
Chang
T
T
Whitfield
L R
LR
D000818:Animals; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005493:Folic Acid Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D011799:Quinazolines / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism; D016597:Trimetrexate
D005493:Folic Acid Antagonists; D011799:Quinazolines; D013431:Sulfates; D016597:Trimetrexate