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 pharmacokinetics of oral mizolastine in order to determine whether the drug concentration in the fluid of suction-induced skin blisters could better predict the antihistamine activity than the plasma concentration.


METHODS
Department of Internal Medicine, Université Paris 6.


METHODS
Ten healthy male volunteers.


METHODS
The volunteers (mean age 26.8 years, mean weight 75.8 kg) received a single 10-mg oral dose of mizolastine at 1000 hours. The pharmacokinetic study included 11 plasma and 9 blister fluid samples and blister epidermal-roof specimens. Mizolastine was assayed by high-performance liquid chromatography (HPLC). Each volunteer also received nine intradermal injections of 5 micrograms histamine. Antihistamine activity was assessed as the post-treatment percentages of changes in the histamine-induced relative wheal and flare areas versus baseline.


RESULTS
Mizolastine mean Cmax (SD) and median tmax were, respectively, 380 ng.ml-1 and 0.8 h in plasma, and 21.8 ng.ml-1 and 10 h in blister fluid. Mizolastine could not be quantified in the epidermis. The maximal histamine-induced relative flare inhibition was 72.5% and was attained at the median time of 3 h post-dosing and therefore was delayed by 2.2 h with respect to the plasma tmax. Mean relative wheal inhibition, although lower, showed the same time profile. A direct relationship could not be found between drug concentrations in blister fluid and antihistamine activity. Simulated concentrations in the peripheral compartment better explain the maximum inhibition effect on flare, observed 3 h post-dosing, with a flatter hysteresis loop obtained when plotting relative flare inhibition versus plasma or blister-fluid drug concentrations.


CONCLUSIONS
The mizolastine concentrations in the skin suction-blister fluid were not predictive of the antihistamine activity.
Chosidow
O
O
Department of Internal Medicine, Hôpital de la Salpêtrière, Université Paris, France.
Dubruc
C
C
Danjou
P
P
Fuseau
E
E
Espagne
E
E
Bianchetti
G
G
Thenot
J P
JP
Herson
S
S
Rosenzweig
P
P
Revuz
J
J
D000284:Administration, Oral; D000328:Adult; D001562:Benzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D001768:Blister / Q000378:metabolism*; D001834:Body Water / Q000378:metabolism*; D006632:Histamine; D006634:Histamine H1 Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D006967:Hypersensitivity; D008297:Male
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C076170:mizolastine; D006632:Histamine