Disposition and metabolism of the antitumor glycoside phyllanthoside in mouse and beagle dog.
Phyllanthoside is a naturally occurring glycoside with activity against IP transplantable murine tumors. Phyllanthoside administered IV, to mice at a nontoxic dose of 16 mg/kg could not be detected in blood or plasma even 30 s after administration. There was rapid formation of a less polar metabolite, which disappeared with a half-life of about 10 min. When phyllanthoside was administered as an IV bolus to beagle dogs at doses of 0.1, 0.5, and 3.0 mg/kg the mean half-life of phyllanthoside elimination from plasma was 1.3 min and total body clearance 85.8 ml min-1 kg-1. A second phase of elimination was seen but could not be accurately defined. Only trace amounts of the less polar metabolite were detected in dog plasma. Infusion of phyllanthoside to beagle dogs at doses of 0.5 and 3.0 mg/kg over 70 min gave values for an initial half-life of 0.3 and 0.6 min, a terminal half-life of 99.4 and 16.5 min, and a total body clearance of 11.2 and 49.2 ml min-1 kg-1, respectively. The highest nontoxic dose of phyllanthoside in dog was 0.1 mg/kg, while doses of 0.5 mg/kg and 3.0 mg/kg resulted in ataxia and death of the dog. There was no difference in toxicity to dog according to whether phyllanthoside was given by IV bolus or continuous infusion. Isolated hepatocytes from rat metabolized phyllanthoside at a rate of 4.4 micrograms/min per 10(6) cells to form the less polar metabolite. Coculture with isolated hepatocytes decreased the cytotoxicity of phyllanthoside to A204 human rhabdomyosarcoma cell line growing in soft agarose. It is suggested that rapid metabolism of phyllanthoside in mouse as against dog might account for the lower toxicity of phyllanthoside in mouse, and might also account for the reported poor antitumor activity of IV-administered phyllanthoside in the mouse.
Moore
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000633:toxicity; D001572:Benzofurans; D004285:Dogs; D006027:Glycosides / Q000378:metabolism* / Q000633:toxicity; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D012717:Sesquiterpenes; D013045:Species Specificity; D013141:Spiro Compounds
D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; D006027:Glycosides; D012717:Sesquiterpenes; D013141:Spiro Compounds; C014754:phyllanthoside