The effects of steady-state erythromycin and azithromycin on the pharmacokinetics of sildenafil in healthy volunteers

Br J Clin Pharmacol. 2002;53 Suppl 1(Suppl 1):37S-43S. doi: 10.1046/j.0306-5251.2001.00031.x.


Aims: Sildenafil, an effective oral treatment for erectile dysfunction, is predominantly metabolized by the cytochrome P450 isozyme 3A4, which is inhibited by a number of the macrolide antibiotics. Therefore, two placebo-controlled, parallel-group studies were conducted to evaluate the effects of multiple doses of erythromycin and azithromycin on the pharmacokinetics, safety and tolerability of a single oral 100-mg dose of sildenafil.

Methods: In the erythromycin interaction study, 26 male volunteers (18--45 years of age) received open-label sildenafil 100 mg on day 1. Half received blinded erythromycin (500 mg) twice daily on days 2--6, and the other half received placebo. On day 6, all subjects received a second 100-mg dose of sildenafil. In the azithromycin interaction study, 24 male volunteers (19--33 years of age) received open-label 100 mg sildenafil on day 1. Half then received blinded azithromycin (500 mg) once daily on days 2--4, and the other half received placebo. On day 4, all subjects received another 100-mg dose of sildenafil. In both studies, blood samples were collected on the first and last study day for the analysis of plasma concentrations of sildenafil and its primary metabolite, UK-103,320.

Results: Repeated dosing with erythromycin caused statistically significant increases in the AUC and Cmax of sildenafil (2.8-fold and 2.6-fold, respectively) but had no effect on Tmax, kel or t1/2. A statistically significant 1.4-fold increase in the AUC of UK-103,320 was also observed, as well as a significant decrease in kel, resulting in an increase of about 1 h in t1/2. In contrast, repeated dosing with azithromycin caused no significant change in any pharmacokinetic parameter of either sildenafil or UK-103,320. Erythromycin, azithromycin and sildenafil were well tolerated; adverse events were mild and transient. No subject withdrew from either trial for any reason related to study drug.

Conclusions: These results indicate that erythromycin modifies the pharmacokinetics of sildenafil by inhibiting its CYP3A4-mediated first-pass metabolism. Given these data, a lower starting dose of sildenafil (25 mg) may be considered for patients receiving erythromycin or other potent CYP3A4 inhibitors. Azithromycin did not affect the pharmacokinetics of sildenafil; therefore, no adjustment in dosage is necessary for patients receiving these drugs concomitantly.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Analysis of Variance
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology*
  • Area Under Curve
  • Azithromycin / administration & dosage
  • Azithromycin / pharmacology*
  • Biological Availability
  • Drug Combinations
  • Erythromycin / administration & dosage
  • Erythromycin / pharmacology*
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / adverse effects
  • Phosphodiesterase Inhibitors / pharmacokinetics*
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Piperazines / pharmacokinetics*
  • Purines
  • Pyrimidinones / pharmacokinetics
  • Sildenafil Citrate
  • Sulfones


  • Anti-Bacterial Agents
  • Drug Combinations
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Pyrimidinones
  • Sulfones
  • UK 103320
  • Erythromycin
  • Azithromycin
  • Sildenafil Citrate