title: The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil.
abstract: The role of the genetically polymorphic CYP3A5 in the metabolism of CYP3A substrates is unclear. We investigated the contributions of the CYP3A4 and CYP3A5 isoforms to the metabolism of the phosphodiesterase type 5 inhibitors (PDE5Is) sildenafil, udenafil, and vardenafil. In vitro incubation studies of sildenafil N-demethylation, udenafil N-dealkylation, and vardenafil N-deethylation were conducted using recombinant CYP3A enzymes and 15 human liver microsome (HLM) preparations with predetermined CYP3A5 genotypes. Recombinant CYP3A4 and CYP3A5 both produced N-desalkyl metabolites of sildenafil, udenafil, and vardenafil. The catalytic efficiency (Cl(int) = V(max)/apparent K(m)) of the rCYP3A5 isoform for vardenafil N-deethylation was about 3.2-fold that of rCYP3A4, whereas the intrinsic clearance rates for N-dealkylation of both sildenafil and udenafil were similar between rCYP3A5 and rCYP3A4. The metabolite formation activity was higher in HLMs heterozygous for the CYP3A5*3 allele (n = 9) than in HLMs homozygous for CYP3A5*3 (n = 6). These findings suggest that CYP3A5 and CYP3A4 play a significant role in the metabolism of PDE5Is. The genetic polymorphism of CYP3A5 may contribute to interindividual variability in the disposition of PDE5Is, especially vardenafil. Further in vivo studies are needed to confirm the effects of CYP3A5 genotypes on the pharmacokinetics of PDE5Is.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea.
authors.forename: Hei-Young
authors.initials: HY
authors.lastname: Ku
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Ahn
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.forename: Minkyung
authors.initials: M
authors.lastname: Oh
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D013450:Sulfones / Q000378:metabolism*; D014227:Triazines / Q000378:metabolism; D000069058:Vardenafil Dihydrochloride; D000096926:Benzenesulfonamides
chemical_list: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D051544:Cytochrome P-450 CYP3A; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human; C419664:udenafil; D000096926:Benzenesulfonamides