title: Circadian time-effect of orally administered loratadine on plasma pharmacokinetics in mice.
abstract: Little is known about the chronopharmacokinetics of loratadine, a long-acting tricyclic antihistamine H(1) widely used in the treatment of allergic diseases. Hence, the pharmacokinetics of loratadine and its major metabolite, desloratadine, were investigated after a 20 mg/kg dose of loratadine had been orally administered to comparable groups of mice (n=33), synchronized for three weeks to 12 h light (rest span)/12 h dark (activity span). The drug was administered at three different circadian times (1, 9, and 17 h after light onset [HALO]). Multiple blood samples were collected over 48 h, and plasma concentrations of loratadine and desloratadine were determined by high performance liquid chromatography. There were no significant differences in T(max) of loratadine and desloratadine between treatment-time different groups. However, the elimination half-life (t1/2) of the parent compound and its metabolite was significantly longer (p<0.01) following administration at 9 HALO (t1/2 loratadine and desloratadine 5.62 and 4.08 h at 9 HALO vs. 4.29 and 2.6 h at 17 HALO vs. 3.26 and 3.27 at 1 HALO). There were relevant (p<0.05) differences in C(max) between the three treated groups for loratadine and desloratadine; 133.05+/-3.55 and 258.07+/-14.45 ng/mL at 9 HALO vs. 104.5+/-2.61 and 188.62+/-7.20 ng/mL at 1 HALO vs. 94.33+/-20 and 187.75+/-10.79 ng/mL at 17 HALO. Drug dosing at 17 HALO resulted in highest loratadine and desloratadine total apparent clearance values: 61.46 and 15.97 L/h/kg, respectively, whereas loratadine and desloratadine clearances (CL) were significantly slower (p<0.05) at the other administration times (loratadine and desloratadine CL was 57.3 and 14.22 L/h/kg at 1 HALO vs. 43.79 and 12.89 L/h/kg at 9 HALO, respectively). The area under the concentration-time curve (AUC) of loratadine and desloratadine was significantly (p<0.05) greater following drug administration at 9 HALO (456.75 and 1550.57 (ng/mL) . h, respectively); it was lowest following treatment at 17 HALO (325.39 and 1252.53 (ng/mL) . h, respectively). These pharmacokinetic data indicate that the administration time of loratadine significantly affected its pharmacokinetics: the elimination of loratadine and its major metabolite desloratadine.
authors.affiliation: Laboratoire de Pharmacologie, Faculte de Medecine, Monastir, Tunisie.
authors.forename: Dorra
authors.initials: D
authors.lastname: Dridi
authors.forename: Mossadok
authors.initials: M
authors.lastname: Ben-Attia
authors.forename: Mamane
authors.initials: M
authors.lastname: Sani
authors.forename: Nassim
authors.initials: N
authors.lastname: Djebli
authors.forename: Francois Ludovic
authors.initials: FL
authors.lastname: Sauvage
authors.forename: Naceur A
authors.initials: NA
authors.lastname: Boughattas
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002138:Calibration; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D017336:Loratadine / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D015203:Reproducibility of Results; D013997:Time Factors
chemical_list: D018926:Anti-Allergic Agents; D017336:Loratadine