PHARMACOKINETICS OF PENTAZOCINE AND ITS OCCUPANCY OF OPIOID RECEPTORSIN RAT-BRAIN

In order to assess quantitatively the pharmacodynamic process of penta zocine (PTZ), time courses of its plasma concentration and of the occu pation of specific opioid receptors in the brain were investigated aft er intravenous (i.v.) administration of PTZ to rats. The plasma concen tration of PTZ was determined by HPLC and the pharmacokinetic paramete rs were analyzed using nonlinear least-squares analysis. Measurement o f ex vivo receptor occupation was made by comparing the specific [H-3] naloxone (opioid receptor antagonist) binding in vitro to the crude P- 2-synaptosomal fractions between vehicle-treated rats (control) and PT Z-treated rats. Following the i.v. administration of PTZ, the occupanc y of specific opioid receptors decreased rapidly until 10 min, dependi ng on the two pharmacological doses (2.5 and 10 mg/kg). The results st rongly suggest the fast binding kinetics of PTZ in terms of its associ ation with and dissociation from specific opioid receptor sites in the brain in addition to its fast rate of disappearance from the brain co mpartment. Furthermore, me demonstrated that the time profile of recep tor occupancy correlated well (r = 0.8650) with that of the unbound co ncentration in plasma until 120 min after the i.v. administration of P TZ to rats.