Interspecies variability of TNP-470 metabolism, using primary monkey, rat, and dog cultured hepatocytes.
The biotransformation of TNP-470 [O-(chloroacetylcarbamoyl)fumagillol; AGM 1470], a potent in vitro inhibitor of angiogenesis, was investigated in primary cultured hepatocytes isolated from different species, including monkey, dog, and rat, as well as in microsomal fractions of various monkey tissues. Previous metabolic studies by our group using human hepatocytes in primary culture demonstrated that TNP-470 was primarily metabolized to M-IV through an ester cleavage, with subsequent conversion of M-IV to M-II by microsomal epoxide hydrolase. Additional studies using monkey liver microsomes demonstrated that M-II was then glucuronidated by uridine-5'-diphosphoglucuronyl transferase, leading to the formation of M-III. Three other, as yet unidentified, metabolites, labeled M-I, M-V, and M-VI, were also detected. Similarly to findings in human hepatocytes, the predominant extracellular metabolite was M-II in all species studied. Minor interspecies variability was observed in the total amount of drug biotransformed by hepatocytes, but some variability was detected in the metabolic pattern of TNP-470 in monkey hepatocytes, compared with rat or dog hepatocytes. In monkey hepatocytes, as previously observed in human cells, TNP-470 was metabolized to six derivatives, labeled M-I, M-II, M-III, M-IV, M-V, and M-VI, whereas the latter metabolite was not observed in dog or rat extracellular medium. Extrahepatic metabolism of TNP-470 was also studied using monkey intestine, kidney, and lung microsomes, which demonstrated that, under these experimental conditions, TNP-470 was extensively metabolized to four derivatives, i.e. M-I, M-II, M-III, and M-IV, with M-III being detected only in liver samples. These studies suggest that the metabolism of TNP-470 in monkeys appears to be most closely related to that observed in humans. Although the individual quantitative metabolic profiles were quite different in various animal species, only one metabolite, namely M-VI, was not detected in either dog or rat hepatocytes in vitro.
Placidi
L
L
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294-0019, USA.
Scott
E C
EC
de Sousa
G
G
Rahmani
R
R
Placidi
M
M
Sommadossi
J P
JP
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D003510:Cyclohexanes; D004285:Dogs; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008861:Microsomes / Q000378:metabolism; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000378:metabolism*; D013045:Species Specificity; D014316:Tritium
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D014316:Tritium; D000077609:O-(Chloroacetylcarbamoyl)fumagillol