RT Journal Article
SR Electronic
T1 Interspecies Variability of TNP-470 Metabolism, Using Primary Monkey, Rat, and Dog Cultured Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 94
OP 99
VO 25
IS 1
A1 Laurent Placidi
A1 Erika Cretton Scott
A1 Georges de Sousa
A1 Roger Rahmani
A1 Michel Placidi
A1 Jean-Pierre Sommadossi
YR 1997
UL http://dmd.aspetjournals.org/content/25/1/94.abstract
AB The biotransformation of TNP-470 [O-(chloroacetylcarbamoyl)fumagillol; AGM 1470], a potentin 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. The American Society for Pharmacology and Experimental Therapeutics