Metabolism of L-[guanidinooxy-14C]canavanine in the rat.
The metabolism of L-canavanine, a nonprotein amino acid with significant antitumor effects, was investigated. L-Canavanine, provided at 2.0 g/kg, was supplemented with 5 microCi of L-[guanidinooxy-14C]canavanine (58 microCi/mumol) and administered iv, sc, or orally to female Sprague-Dawley rats weighing approximately 200 g. 14C recovery in the urine at 24 hr was 83, 68, or 61%, respectively, of the administered dose. Another 5-8% of the 14C was expired as 14CO2. The gastrointestinal tract contained 21% of orally administered 14C. Serum, feces, tissues, and de novo synthesized proteins only accounted for a few percent of the original dose by any administrative route. Analysis of the 14C-containing urinary metabolites revealed that [14C] urea accounted for 88% of the urinary radioactivity for an iv injection, 75% for sc administration, and 50% following an oral dose. By all routes of administration, [14C]guanidine represented 5% of the radioactivity in the urine and [14C]guanidinoacetic acid accounted for 2%. Serum and urine amino acid analysis showed a markedly elevated ornithine level. Basic amino acids such as histidine, lysine, and arginine were also higher in the urine. Plasma ammonia levels were determined following oral canavanine doses of 1.0, 2.0, and 4.0 g/kg. A rapid but transient elevation in plasma ammonia was observed only at the 4.0 g/kg dose. This indicates that elevated plasma ammonia is not a likely cause of canavanine toxicity at the drug concentrations used in this study.
Thomas
D A
DA
Graduate Center for Toxicology, University of Kentucky, Lexington 40506.
Rosenthal
G A
GA
D000284:Administration, Oral; D000596:Amino Acids / Q000097:blood / Q000652:urine; D000641:Ammonia / Q000097:blood; D000818:Animals; D002172:Canavanine / Q000493:pharmacokinetics* / Q000633:toxicity; D002250:Carbon Radioisotopes / Q000652:urine; D005260:Female; D007279:Injections, Subcutaneous; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D002250:Carbon Radioisotopes; D002172:Canavanine; D000641:Ammonia