title: Pharmacokinetic and biopharmaceutical studies on azelastine hydrochloride in beagle dogs by quantitative selected-ion monitoring.
abstract: A quantitative selected-ion monitoring method for the determination of plasma concentrations of the new potent antiallergic agent, 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone hydrochloride (azelastine hydrochloride, A 5610), using N-methyl deuterium labelled azelastine as the internal standard, has been developed. This specific method has a lower limit of sensitivity of about 0.5 ng/ml plasma. The utility of this method was demonstrated by pharmacokinetic studies in the beagle dog after a single oral 20 mg dose as aqueous solution or as sugar-coated tablets, and after a single 10 mg i.v. dose. Plasma concentration-time curves following i.v. dose were satisfactorily described by a bi-exponential equation, and the mean values of half-lives (t 1/2) for the distribution and elimination phases were 17.5 +/- 5.0 min and 160 +/- 14 min, respectively. From the comparison of the areas under the curves after the p.o. dose of aqueous solution and tablet to that after i.v. dose, the absolute availabilities were estimated to be 16.6 +/- 2.5% and 19.6 +/- 0.4%, respectively. These low availabilities could be explained on the basis of a first-pass effect. From the analysis according to the Loo-Riegelman method, the absorption rate was revealed to be described by a first-order process. The absorption half-lives were 48.1 +/- 10.2 min for the solution and 58.4 +/- 21.8 min for the tablet. The lag times before onset of absorption were 18.2 +/- 2.1 min and 40.9 +/- 10.8 min, respectively. This seemed to be due to the difference in gastric emptying time or disintegration time of the tablets in the gastro-intestinal tract.
mesh_terms: D000818:Animals; D001702:Biopharmaceutics; D004285:Dogs; D006634:Histamine H1 Antagonists / Q000097:blood / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010793:Phthalazines / Q000097:blood / Q000378:metabolism*; D011724:Pyridazines / Q000378:metabolism*
chemical_list: D006634:Histamine H1 Antagonists; D010793:Phthalazines; D011724:Pyridazines; C020976:azelastine