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

The pharmacokinetics and pharmacodynamics of ebastine at single oral d oses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma c oncentrations of the active metabolite of ebastine were measured at pr edetermined times after the dose. At these times an intradermal inject ion of 0.01 mL of a 0.2 mg mL(-1) histamine diphosphate solution was g iven, 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). T he mean histamine-induced wheal areas were significantly suppressed fr om 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after th e 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-pharmacodynam ic model was used to analyse the relationship between inhibition of wh eal skin reaction and changes in the active metabolite of plasma conce ntration after ebastine administration. A significant delay of 3-4 h w as present between the maximum effect and the peak plasma concentratio n. Calculated from mean data, the rate constant for equilibration of t he drug between plasma and effect site was 0.17 and 0.22 h(-1) after 1 0 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 maxima l effect was 18.9 +/- 4.8 ng mL(-1) after 10 mg and 18.2 +/- 5.7 ng mL (-1) after 20 mg ebastine.