Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo

J Clin Psychopharmacol. 1996 Apr;16(2):104-12. doi: 10.1097/00004714-199604000-00002.


Biotransformation of the H-1 antagonist terfenadine to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations of human liver. These metabolic reactions are presumed to be mediated by Cytochrome P450-3A isoforms. The azole antifungal agent ketoconazole was a highly potent inhibitor of both reactions, having mean inhibition constants (Ki) of 0.037 and 0.34 microM for desalkyl- and hydroxy-terfenadine formation, respectively. Itraconazole also was a potent inhibitor, with Ki values of 0.28 and 2.05 microM, respectively. Fluconazole, on the other hand, was a weak inhibitor. Six selective serotonin reuptake inhibitor antidepressants tested in this system were at least 20 times less potent inhibitors of terfenadine metabolism than was ketoconazole. An in vitro-in vivo scaling model used in vitro Ki values, typical clinically relevant plasma concentrations of inhibitors, and presumed liver:plasma partition ratios to predict the degree of terfenadine clearance impairment during coadministration of terfenadine with these inhibitors in humans. The model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole. However, fluconazole and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfenadine clearance to a degree that would be of clinical importance. Caution is nonetheless warranted with the coadministration of SSRIs and terfenadine when high doses of SSRIs (particularly fluoxetine) are administered. Also, some individuals may be unusually susceptible to metabolic inhibition for a variety of reasons.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antifungal Agents / pharmacology*
  • Antifungal Agents / toxicity
  • Aryl Hydrocarbon Hydroxylases*
  • Biotransformation / drug effects
  • Culture Techniques
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / physiology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Histamine H1 Antagonists / pharmacokinetics*
  • Histamine H1 Antagonists / toxicity
  • Humans
  • Ketoconazole / pharmacology*
  • Ketoconazole / toxicity
  • Metabolic Clearance Rate / drug effects
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors*
  • Oxidoreductases, N-Demethylating / physiology
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Selective Serotonin Reuptake Inhibitors / toxicity
  • Terfenadine / pharmacokinetics*
  • Terfenadine / toxicity


  • Antifungal Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Histamine H1 Antagonists
  • Serotonin Uptake Inhibitors
  • Terfenadine
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Ketoconazole