The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil.
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Ku HY, Ahn HJ, Seo KA, Kim H, Oh M, Bae SK, Shin JG, Shon JH, Liu KH
The contributions of cytochromes P450 3A4 and 3A5 to the metabolism of the phosphodiesterase type 5 inhibitors sildenafil, udenafil, and vardenafil.
Drug Metab Dispos. 2008 Jun;36(6):986-90. doi: 10.1124/dmd.107.020099. Epub 2008 Feb 28.
- PubMed ID
- 18308836 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Sildenafil Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Sildenafil Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Udenafil Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Udenafil Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Vardenafil Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Vardenafil Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareVardenafilEverolimus The metabolism of Vardenafil can be decreased when combined with Everolimus. VardenafilEtoposide The metabolism of Vardenafil can be decreased when combined with Etoposide. VardenafilIsavuconazole The metabolism of Vardenafil can be decreased when combined with Isavuconazole. VardenafilAldesleukin The metabolism of Vardenafil can be decreased when combined with Aldesleukin. VardenafilOctreotide The metabolism of Vardenafil can be decreased when combined with Octreotide.
