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

  • Nicolas J
  • Whomsley R
  • Collart P
 et al. 
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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 6β- hydroxylation (IC50of 23, 21 and 32 μM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50of 18, 36 and 15 μM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)- mephenytoin 4-hydroxylation (K(i) of 0.17 μM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide hydroxylation (ca. 3-fold increase at 30 μM) and inhibited some glucuronidation enzymes. Mizolastine appeared to be a relatively weak and unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50s in the 100 μmolar 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.

Author-supplied keywords

  • Antihistamines
  • Cytochrome P-450
  • Drug-drug interactions
  • Glucuronidation enzymes

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  • Jean Marie Nicolas

  • Rhys Whomsley

  • Philippe Collart

  • Jose Roba

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