Disposition of [14C]velnacrine maleate in rats, dogs, and humans.

This study describes the disposition of [14C]velnacrine maleate in rats, dogs, and humans, and the isolation and identification of metabolites in dog urine. Following oral administration of [14C]velnacrine maleate, drug-related material was well absorbed in all three species, with the majority of the dose recovered in the urine. Fecal elimination of radioactivity accounted for the remainder of the dose. The majority of the radioactivity was eliminated within 24 hr. Pharmacokinetic parameters for the elimination of radioactivity from the plasma of rats and dogs were similar after oral dosing compared with intravenous dosing. In humans, the plasma and urinary levels of velnacrine maleate were substantially lower, and the elimination half-life shorter than for total radioactivity, indicating the presence of one or more metabolites with a longer half-life than the parent compound. Preliminary TLC analysis of urine, plasma, and feces showed that metabolism appeared to be similar in the three species investigated. Velnacrine maleate was extensively metabolized with only approximately 10%, 19%, and 33% of the dose appearing in the urine as unchanged drug in humans, dogs, and rats, respectively. Isolation and identification of dog urinary metabolites was conducted. The identity of the isolated metabolites was determined by GC/MS and proton NMR. One of the main metabolic routes was found to be via hydroxylation of the tetrahydroaminoacridine ring with other minor hydroxylated and dihydroxylated metabolites being detected. In addition two dihydrodiol metabolites were also identified. Phase II metabolism did not appear to be a significant route.

Metabolism and pharmacokinetics of 14C-pentoxifylline in healthy volunteers.

The metabolism and pharmacokinetics of 14C-pentoxifylline (Trental) have been studied in three healthy male volunteers after oral administration of 200 mg (50 microCi). The radiolabelled drug was rapidly absorbed and by 6 h 89.1 +/- 2.4% of the 14C material was excreted in the urine. The dosed 14C material (96.9 +/- 2.2%) was recovered in excreta by 24 h with 93.3 +/- 2.3% in the urine 3.0 +/- 0.2% in the faeces. Peak plasma levels of radioactivity (4.1-6.2 micrograms eq ml-1) occurred 0.25-0.75 h after administration. This radioactivity decayed in a biexponential fashion with an initial half-life of 1.01 +/- 0.13 h and a terminal half-life of 36.06 +/- 16.94 h. The peak plasma levels (0.48-2.25 micrograms ml-1) of parent drug, as measured using a specific gas chromatographic assay also occurred at 0.25-0.75 h and subsequently decayed extremely rapidly with an initial half-life of 0.18 +/- 0.15 h and terminal half-life of 0.76 +/- 0.44 h. Urinary 14C-labelled metabolites were separated by semi-preparative high performance liquid chromatography and characterised by mass spectrometry and by comparison with authentic synthetic compounds. Of the dosed 14C-pentoxifylline, greater than 90% could be identified as characterised metabolites in urine.