PLASMA AND SKIN SUCTION-BLISTER-FLUID PHARMACOKINETICS AND TIME-COURSE OF THE EFFECTS OF ORAL MIZOLASTINE

Objective: To investigate plasma and skin suction-blister-fluid pharma cokinetics of oral mizolastine in order to determine whether the drug concentration in the fluid of suction-induced skin blisters could bett er predict the antihistamine activity than the plasma concentration. S etting: Department of Internal Medicine, University Paris 6. Subjects: Ten healthy male volunteers. Methods: The volunteers (mean age 26.8 y ears, mean weight 75.8 kg) received a single 10-mg oral dose of mizola stine at 1000 hours. The pharmacokinetic study included 11 plasma and 9 blister fluid samples and blister epidermal-roof specimens. Mizolast ine was assayed by high-performance liquid chromatography (HPLC). Each volunteer also received nine intradermal injections of 5 mu g histami ne. Antihistamine activity was assessed as the post-treatment percenta ges of changes in the histamine-induced relative wheal and flare areas versus baseline. Results: Mizolastine mean C-max (SD) and median t(ma x) were, respectively, 380 ng . ml(-1) and 0.8 h in plasma, and 21.8 n g . ml(-1) and 10 h in blister fluid. Mizolastine could not be quantif ied in the epidermis. The maximal histamine-induced relative flare inh ibition was 72.5% and was attained at the median time of 3 h post-dosi ng and therefore was delayed by 2.2 h with respect to the plasma t(max ). Mean relative wheal inhibition, although lower, showed the same tim e profile. A direct relationship could not be found between drug conce ntrations in blister fluid and antihistamine activity. Simulated conce ntrations in the peripheral compartment better explain the maximum inh ibition effect on flare, observed 3 h post-dosing, with a flatter hyst eresis loop obtained when plotting relative flare inhibition versus pl asma or blister-fluid drug concentrations. Conclusion: The mizolastine concentrations in the skin suction-blister fluid were not predictive of the antihistamine activity.