Species-differences in disposition and reductive metabolism of methoxymorpholinodoxorubicin (PNU 152243), a new potential anticancer agent

Plasma pharmacokinetics, excretion balance and urinary metabolites of metho xymorpholino doxorubicin (MMDX) were investigated in male and female rats a nd in female dogs after i.v. administration of the C-14-labelled drug. The mean total recovery of radioactivity in 96 h (urine plus faeces) was approx imately 74 and 60% dose in male and female rats, respectively, while in fem ale dogs approximately 72% dose was recovered in 336 h. Most of the radioac tivity was present in faeces, with the urinary elimination accounting for o nly 3-4% dose in rats and dogs. These data suggest that biliary excretion i s an important route of elimination of MMDX and/or its metabolites in both species. No differences were observed in the urinary metabolic profile of m ale and female rats. Two main peaks were present in radiochromatograms of u rine from rats and dogs, i.e, MMDX and its 13-dihydro metabolite (MMDX-ol), accounting for approximately 25 and 20% of total radioactivity in 0-24-h u rine in rats and 30 and 36% in dogs. The MMDX-ol/MMDX ratio in dog urine wa s higher than that observed in rat urine. No aglycones were detected in the urine samples from either species. In the rat, the plasma concentration-ti me profile suggested that the disposition of MMDX, MMDX-ol and total radioa ctivity is not sex-dependent. MMDX was the major species present in the sys temic circulation; its AUC (0-96 h) accounted for 70% of total plasma radio activity with the sum of AUC (MMDX) plus AUC (MMDX-ol) accounting for 77% o f total radioactivity. In the dog, the sum of AUC (MMDX) plus AUC (MMDX-ol) amounted to 8% of radioactivity AUC(0-t(z)) indicating that an important p roportion of other(s) unknown metabolite(s) is present in dog plasma. Plasm a levels of MMDX-ol in the rat were approximately 10-fold lower than those of the parent compound, whereas they were three times higher than those of MMDX in the dog. These data show that the reduction of the 13-keto group of MMDX is species-dependent, and occurs preferentially in the dog compared t o the rat. (C) 2000 Academic Press.