L. Placidi et al., INTERSPECIES VARIABILITY OF TNP-470 METABOLISM, USING PRIMARY MONKEY,RAT, AND DOG CULTURED-HEPATOCYTES, Drug metabolism and disposition, 25(1), 1997, pp. 94-99
The biotransformation of TNP-470 [O-(chloroacetylcarbamoyl)fumagillol;
AGM 1470], a potent in vitro inhibitor of angiogenesis, was investiga
ted in primary cultured hepatocytes isolated from different species, i
ncluding monkey, dog, and rat, as well as in microsomal fractions of v
arious monkey tissues. previous metabolic studies by our group using h
uman hepatocytes in primary culture demonstrated that TNP-470 was prim
arily metabolized to M-IV through an ester cleavage, with subsequent c
onversion of M-IV to M-ll 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-lll. Three other, as yet unidentified, metabolit
es, labeled M-l, M-V, and M-VI, were also detected. Similarly to findi
ngs in human hepatocytes, the predominant extracellular metabolite was
M-ll in all species studied. Minor interspecies variability was obser
ved in the total amount of drug biotransformed by hepatocytes, but som
e variability was detected in the metabolic pattern of TNP-470 in monk
ey hepatocytes, compared with rat or dog hepatocytes. In monkey hepato
cytes, as previously observed in human cells, TNP-470 was metabolized
to six derivatives, labeled M-l, M-II, M-lll, M-IV, M-V, and M-VI, whe
reas the latter metabolite was not observed in dog or rat extracellula
r medium. Extrahepatic metabolism of TNP-470 was also studied using mo
nkey intestine, kidney, and lung microsomes, which demonstrated that,
under these experimental conditions, TNP-470 was extensively metaboliz
ed to four derivatives, i.e. M-l, M-ll, M-Ill, and M-IV, with M-Ill be
ing detected only in liver samples. These studies suggest that the met
abolism of TNP-470 in monkeys appears to be most closely related to th
at observed in humans. Although the individual quantitative metabolic
profiles were quite different in various animal species, only one meta
bolite, namely M-VI, was not detected in either dog or rat hepatocytes
in vitro.