Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man

1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after s ingle intravenous and/or oral doses of sildenafil or [C-14]-sildenafil (Via gra(TM)). 2. In man, absorption from the gastrointestinal tract was essentially compl ete. With the exception of male rat, T-max occurred at similar to 1 h or le ss. Bioavailability was attenuated by presystemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-21/kg) b ut was greater in dog (5.21/kg), due to lower plasma protein binding (84 ve rsus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-l ives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resu lted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the vario us species. 5. After single oral or intravenous doses of [C-14]-sildenafil, the majorit y of radioactivity was excreted in the faeces of all species. No unchanged drug was deterred in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-d emethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring a nd aliphatic hydroxylation. Additional metabolites arose through combinatio ns of these pathways. 7. Sildenafil was the major component detected in human plasma. Following o ral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N, N'-desethyl metabolites were 55 and 27 % that of parent compound respective ly.