Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine. Formation of descarboethoxyloratadine by CYP3A4 and CYP2D6

Biochem Pharmacol. 1996 Jan 26;51(2):165-72. doi: 10.1016/0006-2952(95)02169-8.


[3H]Loratadine was incubated with human liver microsomes to determine which cytochrome P450 (CYP) enzymes are responsible for its oxidative metabolism. Specific enzymes were identified by correlation analysis, by inhibition studies (chemical and immunoinhibition), and by incubation with various cDNA-expressed human P450 enzymes. Descarboethoxyloratadine (DCL) was the major metabolite of loratadine detected following incubation with pooled human liver microsomes. Although DCL can theoretically form by hydrolysis, the conversion of loratadine to DCL by human liver microsomes was not inhibited by the esterase inhibitor phenylmethylsulfonyl fluoride (PMSF), and was dependent on NADPH. A high correlation (r2 = 0.96, N = 10) was noted between the rate of formation of DCL and testosterone 6 beta-hydroxylation, a CYP3A-mediated reaction. With the addition of ketoconazole (CYP3A4 inhibitor) to the incubation mixtures, the residual rate of formation of DCL correlated (r2 = 0.81) with that for dextromethorphan O-demethylation, a CYP2D6 reaction. Rabbit polyclonal antibodies raised against the rat CYP3A1 enzyme (5 mg IgG/nmol P450) and troleandomycin (0.5 microM), a specific inhibitor of CYP3A4, decreased the formation of DCL by 53 and 75%, respectively, when added to 1.42 microM loratadine microsomal incubations. Quinidine (5 microm), a CYP2D6 inhibitor, inhibited the formation of DCL approximately 20% when added to microsomal incubations of loratadine at concentrations of 7-35 microM. Incubation of loratadine with cDNA-expressed CYP3A4 and CYP2D6 microsomes catalysed the formation of DCL with formation rates of 135 and 633 pmol/min/nmol P450, respectively. The results indicated that loratadine was metabolized to DCL primarily by the CYP3A4 and CYP2D6 enzymes in human liver microsomes. In the presence of a CYP3A4 inhibitor, loratadine was metabolized to DCL by the CYP2D6 enzyme. Conformational and electrostatic analysis of loratadine indicated that its structure is consistent with substrate models for the CYP2D6 enzyme.

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Antifungal Agents / pharmacology
  • Antimalarials / pharmacology
  • Binding Sites
  • Biotransformation
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / analysis*
  • Histamine H1 Antagonists / metabolism*
  • Humans
  • In Vitro Techniques
  • Ketoconazole / pharmacology
  • Loratadine / metabolism*
  • Microsomes, Liver / enzymology*
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / analysis*
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Models, Molecular
  • Oxidation-Reduction
  • Piperidines / analysis*
  • Pyridines / analysis*
  • Quinidine / pharmacology
  • Recombinant Proteins / antagonists & inhibitors
  • Substrate Specificity
  • Troleandomycin / pharmacology


  • Anti-Bacterial Agents
  • Antifungal Agents
  • Antimalarials
  • Cytochrome P-450 Enzyme Inhibitors
  • Histamine H1 Antagonists
  • Piperidines
  • Pyridines
  • Recombinant Proteins
  • Loratadine
  • Cytochrome P-450 Enzyme System
  • Troleandomycin
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • desloratadine
  • Quinidine
  • Ketoconazole