Pharmacokinetics of azelastine and its active metabolite, desmethylazelastine, in guinea pigs

Pharmacokinetics of azelastine (AZ) and its major active metabolite desmethylazelastine (DAZ) after iv or po administration of 1 mg/kg [14C]AZ hydrochloride or unlabeled AZ hydrochloride were studied in guinea pigs. Total 14C radioactivity concentrations in blood, plasma, lung, urine, and feces were determined by liquid scintillation counting. AZ and DAZ concentrations in the plasma and lung samples were determined by HPLC methods. For pharmacokinetic modeling, the mean concentrations of AZ and DAZ in plasma were converted to those in blood. Following the iv or po dose, AZ blood concentrations declined biexponentially with the distribution and elimination phases. The open two- and one-compartment models for AZ and DAZ concentrations in blood, respectively, and the open one-compartment model for the two compounds in lung tissue describe the experimental data reasonably well. The apparent volume of distribution of AZ suggested that the drug was widely distributed in the body. The mean lung/blood concentration ratios, which varied from 14.2 to 20.1 in the iv- and po-dosed animals for AZ and from 96.7 to 140.3 in the iv- and po-dosed groups for DAZ, respectively, indicate the capacity of the lung ("target tissue") for preferential uptake of the drug and its active metabolite. The efficiency of the desmethyl metabolite uptake into the lung was about 6-fold greater than that of AZ. The clearance of AZ from the body was faster than that of DAZ following either po or iv administration. The estimated availability of the AZ oral dose in guinea pigs was 0.19, which suggested that AZ was subjected to an extensive hepatic first-pass metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)