Biotransformation of sildenafil in the male rat

Evaluation of drug interactions with testosterone and carbamazepine

Ying Ku Lin, Ming Thau Sheu, Thau Zong Tzen, Hsiu O. Ho

Research output: Contribution to journalArticle

Abstract

The biotransformation of sildenafil to its major circulating metabolite, UK-103,320, was studied in male rat liver microsomes. The conversion of sildenafil to UK-103,320 by rat microsomes followed Michaelis-Menten kinetics, for which the parameters were Vmax = 1.96 μM/minand Km = 27.31 μM. Using substrates of CYP3A4 of testosterone and carbamazepine, the active sites on CYP3A4 responsible for metabolizing sildenafil were also evaluated. Sildenafil biotransformation was inhibited in the individual presence of testosterone and carbamazepine. The results showed drug interaction was observed in the sildenafil-testosterone and sildenafil-carbamazepine. Although testosterone and carbamazepine can inhibit sildenafil demethylation in concentration- and incubation time-dependent manners, sildenafil did not inhibit testosterone hydroxylation or carbamazepine epoxidation. These results may be explained by a model in which multiple substrates or ligands can concurrently bind to the active site of a single CYP3A4 molecule. However, the contribution of separate allosteric sites and conformational heterogeneity to the atypical kinetics of CYP3A4 cannot be ruled out in this study.

Original languageEnglish
Pages (from-to)1219-1226
Number of pages8
JournalDrug Development and Industrial Pharmacy
Volume34
Issue number11
DOIs
Publication statusPublished - Nov 2008

Fingerprint

Drug interactions
Carbamazepine
Biotransformation
Drug Interactions
Testosterone
Rats
Cytochrome P-450 CYP3A
Catalytic Domain
Allosteric Site
Hydroxylation
Kinetics
Epoxidation
Sildenafil Citrate
Liver Microsomes
Substrates
Metabolites
Microsomes
Liver
Ligands
Molecules

Keywords

  • Carbamazepine
  • CYP3A4
  • Drug interaction
  • Sildenafil
  • Testosterone

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

Cite this

Biotransformation of sildenafil in the male rat : Evaluation of drug interactions with testosterone and carbamazepine. / Lin, Ying Ku; Sheu, Ming Thau; Tzen, Thau Zong; Ho, Hsiu O.

In: Drug Development and Industrial Pharmacy, Vol. 34, No. 11, 11.2008, p. 1219-1226.

Research output: Contribution to journalArticle

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