Jen Yeh

This study investigated the metabolism and pharmacokinetics of cetirizine, a new H1-receptor antagonist. Single oral doses of 14C-cetirizine dihydrochloride (10 mg) in aqueous solution were administered to six healthy male volunteers. The drug was rapidly absorbed: The peak mean concentration of radioactivity (359 ng-equivalents/mL) and of unchanged drug (341 ng/mL) were achieved within one hour. Mean concentrations of cetirizine declined biexponentially and had a mean elimination half-life of 7.4 hours. The drug was excreted quite rapidly, with 60% of the dose recovered in the 24-hour urine. An additional 10% was excreted in urine over the next four days. Approximately 10% of the dose was excreted in feces over the five-day study period. The dose was excreted mainly as the unchanged drug. Examination of the radioactive compounds present in the plasma, and excreted in the urine and feces indicate that there is little metabolism of cetirizine. One minor metabolite, formed by oxidative O-dealkylation of the cetirizine side chain, was detected in plasma and feces.

Contact inhibition of replication of the established mammalian cell line 3T3 was examined during growth of the colony and compared with that of the Chinese-hamster cell line CHL-1. The growth curves of cells in the colonies conformed to the predicted exponential and linear rates for CHL-1 and 3T3 respectively. Autoradiographs of colonies in which DNA was labeled with tritiated thymidine showed that in 3T3 colonies, only peripheral cells were labeled, while CHL-1 colonies were labeled throughout.

Confluent 3T3 cultures make and release into the medium a diffusible factor which sustains the state of contact inhibition of replication. Evidence is given that the factor is a specific and reversible inhibitor of the RNA synthesis which precedes cellular replication.

OBJECTIVE: To establish whether the antihistamine cetirizine has the potential to prolong the QTc interval in normal volunteers at up to six times the usual recommended dose. METHODS: Twenty-five healthy volunteers were studied in a prospective, double-blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTc prolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration-time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs. RESULTS: Analysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTc compared with baseline. A paired Student t test showed no difference in dose/area under the concentration-time curve between the 20 mg/day and 60 mg/day dosing groups at steady state. CONCLUSION: In healthy volunteers, cetirizine does not prolong the QTc interval at doses of up to six times the usual recommended dose.

H1-receptor antagonists appear to be absorbed rapidly after oral administration, with peak serum concentrations being reached one to three hours after a dose. For most of these drugs, the absolute bioavailability is unknown because no intravenous formulations are available for comparative purposes. The serum elimination half-life values of these agents are variable: a few hours for terfenadine and triprolidine; about 9 hours for cetirizine, azatadine, and loratadine; from 20 to 25 hours for hydroxyzine, chlorpheniramine, and brompheniramine; and from 5 to 14 days for astemizole. Few pharmacokinetic studies of H1-receptor antagonists in children have been reported. However, it is known that chlorpheniramine, hydroxyzine, cetirizine, and terfenadine have shorter elimination half-life values in children than in adults. Regardless of the age of patients, for most of the H1-receptor antagonists the apparent volumes of distribution and total body clearances appear to be large (3.4 to 18.5 L/kg and 4.4 to 32.1 mL/min/kg, respectively). Cetirizine is an exception, with values of 0.8 L/kg and 0.5 mL/min/kg. Urinary excretion of unchanged antihistamine is higher after cetirizine (60% of dose) than any other H1 blocker. For H1-receptor antagonists with long half-life values, steady state may not be reached for several days (chlorpheniramine and brompheniramine) or several weeks (astemizole), and significant accumulation of drug occurs if the dosing interval is more frequent than every half-life. There is no evidence for the introduction of metabolism of H1-receptor antagonists, even after months of treatment.