Murine chronotoxicity to the antiallergic agent, cetirizine.
Cetirizine is a second-generation histamine H1-receptor antagonist used in the treatment of allergic diseases. The aim of the study was to assess whether cetirizine toxicity estimated by, for example, death, body loss, and leucopenia, is circadian rhythm dependent. A total of 210 male Swiss mice, aged 9 weeks, were synchronized for 3 weeks to 12-hour light (i.e., rest span)/12-hour dark (i.e., activity span) cycles. The drug was administered per os (orally). Each lethal (DL(50) = 750 mg/kg) and sublethal (DT(50) = 55 mg/kg) dose was administered to comparable groups of animals at six different circadian time points (1, 5, 9, 13, 17, and 21 hours after light onset; HALO). The death rate was dosing time dependent (P <0.001). Drug dosing at 5 HALO resulted in maximum mortality (76.75%), whereas dosing at 17 HALO resulted in the lowest mortality rate (16.7%). Cosinor analyses validated a statistically significant circadian rhythm in death rate (P < 0.008). Changes in body weight after cetirizine administration were dosing time dependent (P < 0.01), with the dosing time of least effect (-0.7% loss) at 17 HALO and of greatest effect (-7% loss) at 5 HALO. Cosinor analyses validated a statistically significant circadian rhythm in body loss (P < 0.05). A statistically significant decrease in leukocyte number varied, according to antihistamine dosing time (P < 0.01), with the dosing time of least leucopenia (≈-17%) at 17 HALO and of greatest leucopenia (≈-28%) at 5 HALO. The results show that cetirizine dosing time at the midactivity (dark) span seems to be optimal, since it corresponds to the best tolerance.
Dridi
Dorra
D
Laboratoire de Pharmacologie, Faculté de Médecine, Monastir, Tunisie. dadou1us@yahoo.com
Mansour
Hédi Ben
HB
Boughattas
Naceur A
NA
D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000378:metabolism / Q000633:toxicity*; D001831:Body Temperature / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D017332:Cetirizine / Q000633:toxicity*; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D004435:Eating / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D007970:Leukopenia / Q000139:chemically induced / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D013997:Time Factors
D018926:Anti-Allergic Agents; D017332:Cetirizine