Lack of CYP3A inhibition effects of sertindole on terfenadine in healthy volunteers

Int J Clin Pharmacol Ther. 1998 Mar;36(3):146-51.

Abstract

The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of terfenadine was investigated. Thirteen subjects who completed the study received a single 120 mg dose of terfenadine alone or with concomitant 20 mg sertindole daily. The mean values for terfenadine Cmax (alone: 2.42 +/- 1.48 ng/ml, in combination: 2.99 +/- 1.85 ng/ml) and AUC (29.6 +/- 18.9 vs 37.9 +/- 23.4 ng x hr/ml) did not change statistically significant in the presence of sertindole (p > 0.05). Similarly, the mean Cmax (531 +/- 195 vs 506 +/- 190 ng/ml) and AUC (3,728 +/- 1,163 vs 4,003 +/- 1,739 ng x hr/ml) values of carboxyterfenadine did not change statistically significant in the presence of sertindole (p > 0.05). The other pharmacokinetic parameters of terfenadine and carboxyterfenadine such as Tmax, t1/2, as well as the carboxyterfenadine to terfenadine Cmax and AUC ratios did not change in the presence of sertindole. Although terfenadine is a substrate for CYP3A (cytochrome P-450 3A), while sertindole is a substrate for both CYP2D6 and CYP3A4, the results in this study suggest that sertindole, at a clinical dose, is not an inhibitor of the metabolism of terfenadine.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial

MeSH terms

  • Absorption
  • Administration, Oral
  • Adult
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases*
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP2D6 / chemistry
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / chemistry
  • Drug Interactions
  • Female
  • Histamine H1 Antagonists / pharmacokinetics*
  • Histamine H1 Antagonists / pharmacology
  • Humans
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Male
  • Mass Spectrometry
  • Mixed Function Oxygenases / chemistry
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors*
  • Substrate Specificity
  • Terfenadine / pharmacokinetics*
  • Terfenadine / pharmacology

Substances

  • Antipsychotic Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Histamine H1 Antagonists
  • Imidazoles
  • Indoles
  • Terfenadine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • sertindole