title: Metabolism of loratadine and further characterization of its in vitro metabolites.
abstract: The present study demonstrated that in addition to CYP3A4 and CYP2D6, the metabolism of loratadine is also catalyzed by CYP1A1, CYP2C19, and to a lesser extent by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A5. The biotransformation of loratadine was associated with the formation of desloratadine (DL) and further hydroxylation of both DL and the parent drug (loratadine). Based on the inhibition and correlation studies contribution of CYP2C19 in the formation of the major circulating metabolite DL seems to be minor. Reported clinical results suggest that the steady state mean (%CV) plasma Cmax and AUC(24hr) of loratadine were 4.73 ng/ml (119%) and 24.1 ng.hr/ml (157%), respectively, after dosing with 10 mg loratadine tablets for 10 days. High inter-subject variability in loratadine steady-state data is probably due to the phenotypical characteristics of CYP2D6, CYP2C19, and CYP3A4. The relative abundance of CYP3A4 in the human liver exceeds that of CYP2C19 and CYP2D6 and therefore the contribution of CYP3A4 in the metabolism of loratadine should be major (approximately 70%).
authors.affiliation: Pharmaceutical Sciences and Drug Metabolism, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. anima.ghosal@spcorp.com
authors.forename: Anima
authors.initials: A
authors.lastname: Ghosal
authors.forename: Samir
authors.initials: S
authors.lastname: Gupta
authors.forename: Ragu
authors.initials: R
authors.lastname: Ramanathan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Lu
authors.forename: Ai Duen Iris
authors.initials: AD
authors.lastname: Su
authors.forename: Narciso
authors.initials: N
authors.lastname: Alvarez
authors.forename: Shmuel
authors.initials: S
authors.lastname: Zbaida
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Chowdhury
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Alton
mesh_terms: D000284:Administration, Oral; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D017336:Loratadine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000201:enzymology; D011994:Recombinant Proteins / Q000378:metabolism; D013607:Tablets; D053719:Tandem Mass Spectrometry
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D039563:Histamine H1 Antagonists, Non-Sedating; D007527:Isoenzymes; D011994:Recombinant Proteins; D013607:Tablets; D017336:Loratadine; D003577:Cytochrome P-450 Enzyme System; C121345:desloratadine; D007654:Ketoconazole