title: Metabolism of aildenafil in vivo in rats and in vitro in mouse, rat, dog, and human liver microsomes.
abstract: 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.
authors: Shenyang Pharmaceutical University, Shenyang, 110016, China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.
authors: Yan
authors: Y
authors: Li
authors: Linan
authors: L
authors: Wu
authors: Yuan
authors: Y
authors: Gu
authors: Duanyun
authors: D
authors: Si
authors: Changxiao
authors: C
authors: Liu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D058986:Phosphodiesterase 5 Inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013450:Sulfones / Q000378:metabolism*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; C520604:aildenafil; D051544:Cytochrome P-450 CYP3A
keywords: CYP450; LTQ/Orbitrap hybrid mass spectrometry; aildenafil; metabolic pathways; metabolism