E. Crettonscott et al., PHARMACOKINETICS AND METABOLISM OF O-(CHLOROACETYL-CARBAMOYL) FUMAGILLOL (TNP-470, AGM-1470) IN RHESUS-MONKEYS, Cancer chemotherapy and pharmacology, 38(2), 1996, pp. 117-122
The metabolic disposition and pharmacokinetics of TNP-470 were investi
gated in rhesus monkeys following intravenous administration of 5 mg/k
g of [H-3]-TNP-470. Rapid and extensive metabolism of parent drug to s
ix metabolites occurred as demonstrated by the absence of unchanged dr
ug in plasma and urine at time points as early as 6 min after administ
ration. Substantial, yet variable, plasma levels of M-IV were detected
in all three monkeys with a mean C-max value of 3.54 mu M. Five other
metabolites, labeled M-I, M-II, M-III, M-V and M-VI, were also detect
ed in biological fluids of monkeys. M-II, M-V and M-VI exhibited simil
ar kinetic profiles with apparent plasma elimination half-life values
of 0.91 +/- 0.37, 2.42 +/- 0.13 and 1.19 +/- 0.29 h respectively. In c
ontrast, M-I, M-III and M-IV exhibited much shorter apparent plasma ha
lf-life values of 30 min or less. Urinary recovery within 36 h represe
nted only 19.90 +/- 6.09% of the total administered dose. No radioacti
vity was detected beyond 36 h and during a 15-day sample collection pe
riod, suggesting that nonrenal (biliary) elimination of TNP-470 metabo
lites is a predominant excretion route in nonhuman primates. This stud
y provides the first detailed in vivo analysis of TNP-470 metabolism a
nd disposition using an animal model highly predictive of humans, cons
istent with the detection of the same TNP-470 metabolites in human tis
sues. A detailed understanding of TNP-470 metabolism and disposition i
s critical to fully elucidate the pharmacodynamic properties of this n
ew anticancer drug as clinical investigations proceed.