PHARMACOKINETICS AND METABOLISM OF O-(CHLOROACETYL-CARBAMOYL) FUMAGILLOL (TNP-470, AGM-1470) IN RHESUS-MONKEYS

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.