PHARMACOKINETICS AND PHARMACODYNAMICS OF NIKETHAMIDE AFTER ENDOTRACHEAL ADMINISTRATION IN DOGS

Five dogs were anaesthetized by using iv 30 mg.kg-1 Na-pentobarbiturat e. For each dog, the tracheostomy was done and a sterized rubber tube was inserted into the tracheal tract. Through the rubber tube, 10 ml s terized nikethamide (Nik) solution was rapidly injected into the tract via 10 ml syringe and 5 forceful ventilations were performed immediat ely with the aid of a balloon in 30 s. Following tracheal administrati on (ET) of Nik 8.3 or 25 mg.kg-1 in dogs the pharmacokinetics and phar macodynamics were studied. Blood Nik concentrations were determined by phosphorimetric method. It was shown that the absorption of Nik via t racheal tract was very quick. the blood Nik levels were 7.9 and 10.6 m ug.ml-1 at 0.5 min and reached the maxima of 12.8 and 31.9 mug.ml-1, a t 2.5 min, respectively, which was higher than that of iv Nik 8.3 mg.k g-1. Time course of Nik concentrations in plasma after ET 8.3 and 25 m g kg-1 were fitted to a 2-compartment open model with T1/2Ka 0.48 and 0.85 min, T1/2alpha 2.37 and 1.68 min, T1/2beta 114 and 130 min, AUC 1 201 and 2790 mug.min.ml-1, bioavailability 84.7 % and 65.5 %, respecti vely. One minute after iv or ET Nik (8.3 or 25 mg.kg-1), respiration r ate and tidal volume were increased and reached the maxima after 5 min . The recovery of respiration rate and tidal volume were proportional to the blood Nik concentration after 5-45 min with a linear regression coefficient of 0.9. the results indicated that ET Nik may be used ins tead of iv in resusciatation.