Pharmacokinetics and systemic bioavailability of menogaril, an anthracycline antitumor agent, in the mouse, dog, and monkey.
Menogaril is an antitumor agent of the anthracycline type which is less cardiotoxic than doxorubicin in a chronic rabbit model and is active in experimental tumor systems when given by p.o. or parenteral routes. It is currently undergoing i.v. and p.o. Phase II clinical evaluation. We report here the results of pharmacokinetic and systemic bioavailability studies of menogaril in three species (mouse, dog, and monkey). Upon i.v. administration, menogaril plasma concentration-time curves declined in a biexponential (dog) or triexponential (mouse and monkey) manner, with the terminal disposition half-life (t1/2) being considerably shorter in the dog (2.86 +/- 0.47 h) than in the mouse and monkey (21.6 and 19.0 +/- 3.7 h, respectively). The systemic clearance (CL, in liters/h/kg) was highest in mouse (6.2), followed by dog (2.9) and then monkey (1.4). The drug was extensively distributed in all three species, with steady state volumes of distribution being 88.5, 9.8, and 27.9 liters/kg in the mouse, dog, and monkey, respectively. One, two, and three metabolites were detected in the plasma of mice, monkeys, and dogs, respectively, using reverse phase high performance liquid chromatography. The major fluorescent metabolite in all species coeluted with authentic N-demethyl-menogaril; the other two metabolites were present at low concentrations relative to unchanged menogaril and its putative N-demethylated metabolite. One of these metabolites, which was found in both the dog and monkey, eluted with authentic (7R)-nogarol. Mean maximum plasma concentrations of the putative N-demethylmenogaril metabolite were approximately one-tenth those of menogaril in all three species following i.v. drug administration. Upon p.o. treatment, first-pass metabolism or incomplete absorption reduced the systemic bioavailability to 12% in the dog and 33% in the mouse and monkey. N-Demethylmenogaril was the major fluorescent metabolite observed in the plasma of p.o. treated animals. Interspecies comparison of menogaril pharmacokinetic parameters in mice, dogs, monkeys, and humans using allometric techniques indicated that the parameters for mice, monkeys, and humans were highly correlated; in each of these species presystemic metabolism of p.o. administered menogaril reduced its systemic bioavailability to an equivalent extent (30-35%). To determine if metabolically formed N-demethylmenogaril might contribute to the overall antitumor activity of menogaril, we determined the effect of synthetic N-demethylmenogaril on the life span of mice bearing P388 leukemia. Results indicated that the metabolite is marginally active compared to menogaril itself.
Adams
W J
WJ
Drug Metabolism Research, Upjohn Company, Kalamazoo, Michigan 49001.
McGovren
J P
JP
Dalm
E A
EA
Brewer
J E
JE
Hosley
J D
JD
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D003630:Daunorubicin; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D007941:Leukemia P388 / Q000188:drug therapy; D008253:Macaca mulatta; D017290:Menogaril; D051379:Mice; D008815:Mice, Inbred Strains; D009621:Nogalamycin / Q000378:metabolism / Q000493:pharmacokinetics*; D013045:Species Specificity
D000970:Antineoplastic Agents; D017290:Menogaril; D009621:Nogalamycin; D003630:Daunorubicin