Aildenafil, 1-{[3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d] primidin-5-yl)-4-ethoxyphenyl] sulfonyl}-cis-3, 5-dimethylpiperazine, a
phosphodiesterase type V enzyme inhibitor (PDE5I), is under development for treatment of
erectile dysfunction (ED). The purpose of this study was to elucidate metabolism of
aildenafil in vivo in rats and in vitro in mouse, rat, dog, and human liver microsomes. Thirty-one phase I metabolites have been found by LTQ/Orbitrap hybrid mass spectrometry in rat urine, faeces, and bile after
oral administration. Major biotransformation pathways of
aildenafil included N-dealkylation of the
piperazine ring, hydroxylation and dehydrogenation, aliphatic hydroxylation and loss of alkyl group of
piperazine ring. Minor pathways involved hydroxylation on the phenyl ring,
pyrazole N-demethylation, O-deethylation, loss of
piperazine ring (cleavage of N-S bond) and dehydrogenation on the
piperazine ring. Similar metabolic pathways of
aildenafil were observed in the incubations of liver microsomes from mouse, rat, and dog as well as from human. The depletion rate of parent
drug in mouse and rat liver microsomes was significantly different from that in human liver microsomes. The
cytochrome P450 reaction phenotyping analysis was conducted using
isozyme-specific inhibitors. The results indicated that
CYP3A was the main
isoenzyme involved in oxidative metabolism of
aildenafil. Overall, these in vitro and in vivo findings should provide valuable information on possible metabolic behaviours of
aildenafil in humans.