O. Chosidow et al., PLASMA AND SKIN SUCTION-BLISTER-FLUID PHARMACOKINETICS AND TIME-COURSE OF THE EFFECTS OF ORAL MIZOLASTINE, European Journal of Clinical Pharmacology, 50(4), 1996, pp. 327-333
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.