Disposition and metabolism of the colchicine derivative [14C]-ZD6126 in rat and dog.
1. The tissue distribution, disposition and metabolism of ZD6126, a novel vascular targeting agent, were investigated in rat and dog. This paper comprises the findings of several investigations, including rat quantitative whole-body autoradiography (QWBA), rat and dog balance and metabolism (both in intact and bile-duct-cannulated animals), rat enterohepatic recirculation, and comparison of metabolism between young and mature rats. 2. Following intravenous administration of [(14)C]-ZD6126 to rats, quantitative whole-body autoradiography showed that radioactivity was widely distributed, then rapidly eliminated from the body. 3. ZD6126-related material was eliminated primarily in the faeces (approximately 86%) of both species, indicating the importance of biliary clearance. 4. Metabolite profiles from intact and bile-duct-cannulated animals suggest that ZD6126 is cleared primarily by metabolism. In rat, the major metabolites were ZD6126 phenol, its glucuronide and other metabolites consistent with O-demethylation and conjugation. ZD6126 was more extensively metabolized by male than female rats, and also in young compared with mature rats. In dog, metabolism occurred primarily via direct glucuronidation of the active species, ZD6126 phenol. 5. Following intraduodenal infusion of bile containing [(14)C]-ZD6126-related material to bile-duct-cannulated rats, 30% of the radioactivity was subsequently recovered in bile and urine, showing that one or more components in bile are reabsorbed and undergo enterohepatic recirculation.
Partridge
E A
EA
AstraZeneca, Macclesfield, UK. elizabeth.partridge@astrazeneca.com
D'Souza
R A
RA
Lenz
E M
EM
Smith
S M
SM
Clarkson-Jones
J
J
Roberts
D W
DW
D000375:Aging / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D003078:Colchicine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D009928:Organ Specificity; D009943:Organophosphorus Compounds / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D003078:Colchicine