In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines

Chem Biol Interact. 1999 Nov 15;123(1):63-79. doi: 10.1016/s0009-2797(99)00131-3.


Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The most pronounced effects were observed with terfenadine, astemizole and loratadine which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21 and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of 0.17 microM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide hydroxylation (ca. 3-fold increase at 30 microM) and inhibited some glucuronidation enzymes. Mizolastine appeared to be a relatively weak and unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50Ss in the 100 micromolar range). Cetirizine demonstrated no effect on the investigated activities. A comparison of the inhibitory potencies of cetirizine, terfenadine, loratidine, astemizole and mizolastine with their corresponding plasma concentrations in humans suggests that these antihistamines are not likely to interfere with the metabolic clearance of coadministered drugs, with the exception of loratidine, which appears to inhibit CYP2C19 with sufficient potency to warrant additional investigation.

Publication types

  • Comparative Study

MeSH terms

  • Astemizole / pharmacology
  • Benzimidazoles / pharmacology
  • Cetirizine / pharmacology
  • Cytochrome P-450 Enzyme Inhibitors*
  • Dimethyl Sulfoxide / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Kinetics
  • Loratadine / pharmacology
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology*
  • Terfenadine / pharmacology


  • Benzimidazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Histamine H1 Antagonists
  • Isoenzymes
  • mizolastine
  • Loratadine
  • Terfenadine
  • Astemizole
  • Glucuronosyltransferase
  • Cetirizine
  • Dimethyl Sulfoxide