PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF THE HISTAMINE H-1-RECEPTOR ANTAGONIST EBASTINE IN DOGS

The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0.01 mL of a 0.2 mg mL(-1) histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4.38 +/- 1.01 h after 10 mg ebastine and 4.09 +/- 0.74 h after 20 mg ebastine; the distribution volume was 3.99 +/- 0.88 and 3.65 +/- 0.75 L kg(-1) after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0.67 +/- 0.24 L h(-1) kg(-1) and after 20 mg ebastine was 0.63 +/- 0.17 L h(-1) kg(-1). The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0.001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3-4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0.17 and 0.22 h(-1) after 10 and 20 mg ebastine with a half-life of 4.13 and 3.56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18.9 +/- 4.8 ng mL(-1) after 10 mg and 18.2 +/- 5.7 ng mL(-1) after 20 mg ebastine.