title: The disposition of three phosphodiesterase type 5 inhibitors, vardenafil, sildenafil, and udenafil, is differently influenced by the CYP3A5 genotype.
abstract: OBJECTIVE
  This study was conducted to compare the effect of CYP3A5*3 genotype on the disposition of three phosphodiesterase type 5 inhibitors (PDE5Is), vardenafil, sildenafil, and udenafil, because our previous in-vitro microsomal incubation study showed that the relative contribution of CYP3A5 enzyme to their metabolism was different among these PDE5Is.
  
  
  METHODS
  An open-label three-way crossover study was performed with a single oral dose of PDE5Is (20 mg vardenafil, 100 mg sildenafil, or 200 mg udenafil) in 21 healthy men carrying CYP3A5*1/*1, *1/*3, or *3/*3. After each dose, plasma concentrations of the parents and their major metabolites were measured up to 24 or 48 h.
  
  
  RESULTS
  The AUC(∞) and C(max) of vardenafil were 2.9-fold and 3.1-fold higher in CYP3A5*3/*3 carriers than in individuals with CYP3A5*1/*1 (P=0.003 and 0.002, respectively). The AUC(∞) and C(max) of sildenafil were 1.5-fold and 1.7-fold higher in CYP3A5*3/*3 carriers compared with individuals with CYP3A5*1/*1, but the statistical difference of both parameters among genotype groups was not observed. The disposition of udenafil differed little among groups in relation to the CYP3A5*3 allelic variant.
  
  
  CONCLUSIONS
  These results suggest that the disposition of these PDE5Is are differently influenced by the CYP3A5*3 genotype of individual participants. The CYP3A5*3 genotype affects the oral disposition of vardenafil significantly. The pharmacokinetic diversity of PDE5Is in relation to CYP3A5 genotype may lead to the clinical response variation and remains to be evaluated.
authors.affiliation: Department of Pharmacology, PharmacoGenomics Research Center, Inje University College of Medicine, South Korea.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Hei-Young
authors.initials: HY
authors.lastname: Ku
authors.forename: Seol-Youn
authors.initials: SY
authors.lastname: Bae
authors.forename: Min-Kyung
authors.initials: MK
authors.lastname: Oh
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Yeo
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069058:Vardenafil Dihydrochloride; D000096926:Benzenesulfonamides
chemical_list: D051544:Cytochrome P-450 CYP3A; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D000068677:Sildenafil Citrate; D013449:Sulfonamides; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; C510164:CYP3A5 protein, human; C419664:udenafil; D000096926:Benzenesulfonamides