Pharmacokinetics of radiolabelled quinlukast in rats.

摘要

Pharmacokinetics together with in vivo metabolism and elimination of quinlukast, a potential anti-asthmatic and anti-inflammatory drug, were designed in rats. For this purpose, bile duct cannulated rats and an in situ perfused rat liver preparation were employed. (3)H-radiolabelled compound was administered i.v. or loaded to the perfusion medium, respectively. Quinlukast represented the main form of radioactivity determined in plasma; in comparison with the parent drug metabolites were present in lower levels in the systemic circulation. The pharmacokinetic parameters related to the whole animal were calculated from quinlukast rat plasma concentration-time course. The distribution of quinlukast in the body was relatively fast (distribution half-life was approx. 6min), the elimination half-life exceeded 2h. Binding of quinlukast to rat plasma proteins was very high (approx. 99.7%) and this binding influenced distribution volumes of quinlukast. Both the volume of the central compartment and the volume ata steady state were approx. 115 and 430ml, respectively. The experiments showed that the biliary clearance was the major route of elimination of this compound from the systemic circulation of rats. In agreement with the determined elimination half-life approx. 42% of the radioactivity was found in the bile, with <0.5% appearing in the urine. The majority of the eliminated radioactivity in the bile was in the form of polar metabolites; only a small part of the parent compound was determined. Two hours after intravenous administration, polar metabolites - but no parent drug - were detected in the urine.