Toxicity, disposition, and antitumor effects of L-canavanine in the rat

L-Canavanine, a nonprotein amino acid synthesized by higher plants, was only slightly toxic to rats following a single parenteral injection; the LD50 was 6.77 +- 0.42 gkg in rats given a single sc injection. Pharmacokinetic evaluations indicated that canavanine was rapidly eliminated from the rat following a single dose; the systemic clearance value was 0.114 1hr and the T12 β was 1.56 hr. Repeated sc administration of canavanine resulted in more severe toxicity. Histological studies of tissues from canavanine-treated rats revealed pancreatic acinar cell atrophy and fibrosis. Serum amylase and lipase were elevated after a single dose of canavanine; 3 or more daily injections resulted in a decrease in these digestive enzymes. The major metabolite recovered in the urine of rats that received a single 2.0 gkg dose of canavanine containing 5 μCi L[guanidinooxy-14C] canavanine was [14C]urea. Significant amounts of [14C] guanidine and respired 14CO2 were also produced. Administration of 2.0 gkg canavanine daily for 5- or daily for 9-days produced significant inhibition of the growth of a solid rat colon tumor implanted subcutaneously. Increasing the dose to 3.0 gkgday resulted in regression of the tumor; however, cumulative toxicity, indicated by weight losses > 20%, was unacceptable at the higher dose