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%).
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Histamine H1 Antagonists, Non-Sedating/metabolism , Liver/enzymology , Loratadine/metabolism , Administration, Oral , Biotransformation , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme Inhibitors , Drug Interactions , Enzyme Inhibitors/pharmacology , Histamine H1 Antagonists, Non-Sedating/administration & dosage , Histamine H1 Antagonists, Non-Sedating/pharmacokinetics , Humans , Hydroxylation , Isoenzymes/metabolism , Ketoconazole/pharmacology , Liver/drug effects , Loratadine/administration & dosage , Loratadine/analogs & derivatives , Loratadine/pharmacokinetics , Microsomes, Liver/enzymology , Recombinant Proteins/metabolism , Tablets , Tandem Mass SpectrometryABSTRACT
Desloratadine is a non-sedating antihistamine recently approved for the treatment of seasonal allergic rhinitis. The major metabolite of desloratadine in human plasma and urine is the glucuronide conjugate of 3-hydroxydesloratadine. 3-Hydroxydesloratadine-glucuronide is also the major in vitro metabolite of 3-hydroxydesloratadine formed by incubation of 3-hydroxydesloratadine with human liver microsomes supplemented with uridine 5'-diphosphate-glucuronic acid (UDPGA). The metabolite structure was confirmed by LC-MS and LC-MS/MS. Out of ten recombinant human UDP-glucuronosyltransferases (UGTs), UGT1A1, UGT1A3, UGT1A8 and UGT2B15 exhibited catalytic activity with respect to the formation of 3-hydroxydesloratadine-glucuronide. Inhibition studies with known inhibitors of UGT (diclofenac, flunitrazepam and bilirubin) confirmed the involvement of UGT1A1, UGT1A3 and UGT2B15 in the formation of 3-hydroxydesloratadine-glucuronide. The results from this study demonstrated that the in vitro formation of 3-hydroxydesloratadine-glucuronide from 3-hydroxydesloratadine was mediated via UGT1A1, UGT1A3 and UGT2B15 in human liver.
Subject(s)
Glucuronides/metabolism , Glucuronosyltransferase/metabolism , Histamine H1 Antagonists, Non-Sedating/metabolism , Loratadine/analogs & derivatives , Loratadine/metabolism , Bilirubin/pharmacology , Diclofenac/pharmacology , Enzyme Inhibitors/pharmacology , Flunitrazepam/pharmacology , Glucuronosyltransferase/administration & dosage , Glucuronosyltransferase/antagonists & inhibitors , Humans , In Vitro Techniques , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Time FactorsABSTRACT
Contenido: Introduction. Chapitre 1: Methodes experimentales Chapitre 2: Comparaison des phenomenes de precipitation dans les alliages avant et apres deformation plastique a temeperature ambiante Chapitre 3: Les mecanismes des transformations avant et apres la deformation plastique a froid Chapitre 4: Cinetique de precipitation du compose metastable isomorphe de Fe3Si pendant le revenu d'alliages ayant subi ou non une deformation plastique. Conclusions generales.Annexes.Bibliographie.
