BUCCAL DELIVERY OF AN ALPHA(2)-ADRENERGIC RECEPTOR ANTAGONIST, ATIPAMEZOLE, IN HUMANS

Objective: To evaluate the pharmacokinetics, systemic effects and clin ical applicability of buccally administered atipamezole in healthy vol unteers. Methods: The study was carried out in two parts. In the first part, spray preparations of atipamezole hydrochloride in water/alcoho l (50/50) solution were applied on buccal mucosa of six volunteers. Si ngle doses of 5, 10, 20, and 40 mg atipamezole hydrochloride were admi nistered in ascending order during separate sessions. In the second pa rt, nine subjects received single 20 mg doses as buccal spray, intrave nous infusion. or oral solution in randomized order. Results: Values f or area under the concentration-time curve for atipamezole (mean +/- S D) ranged from 26 +/- 4 ng x hr/ml after 5 mg to 112 +/- 21 ng x hr/ml after 40 mg and peak concentrations ranged from 11 +/- 3 ng/ml after 5 mg to 38 +/- 9 ng/ml after 40 mg. Individual peak concentrations wer e mainly measured at 30 and 60 minutes after administration. Mean elim ination half-lives were approximately 1 1/2 hours after every treatmen t. In part two, a mean bioavailability of 33% was calculated for bucca l administration (compared with intravenous), whereas systemic availab ility after an oral dose was <2%. After intravenous administration the mean total clearance, apparent volume of distribution, and eliminatio n half-life were 1.2 L/hr/kg, 2.9 L/kg, and 1.8 hours, respectively. T he intravenous administration of 20 mg atipamezole hydrochloride produ ced a fivefold elevation in mean plasma norepinephrine concentration, a slight and short-lasting elevation in blood pressure and, in most su bjects, increased tension, alertness and restlessness, and sweating. A fter buccal administration, some subjects reported short-lasting restl essness or tension after the 20 and 40 mg doses. No significant change s in heart rare, blood pressure, or plasma catecholamines were observe d. No effects were observed after swallowing of 20 mg atipamezole hydr ochloride. The spray caused local reactions at buccal mucosa. Superfic ial white spots or areas were observed for several hours; these disapp eared gradually. Subjects also reported transient numbness at the appl ication site. Conclusion: Atipamezole hydrochloride is well absorbed s ystemically through oral mucosa. The oral bioavailability of atipamezo le is negligible, probably because of extensive first-pass metabolism.