EFFECT OF IV ANESTHESIA WITH PROPOFOL ON DRUG DISTRIBUTION AND METABOLISM IN THE DOG

We have studied the effect of i.v. anaesthesia with propofol in the emulsion (Intralipid) formulation on drug distribution and metabolism in six dogs using dual-route administration of propranolol as a model compound. Each dog was studied on two consecutive days: day 1 awake and day 2 during propofol anaesthesia (6 mg kg-1 followed by an infusion of 0.8 mg kg-1 min-1). Propofol anaesthesia was associated with reduced intrinsic clearance by 40% (P < 0.05) but no significant difference in systemic clearance or hepatic plasma flow. Propofol produced marked changes in drug distribution; volume of distribution (V(ss)) of propranolol increased 54% from 82.5 (SEM 7.3) litre awake to 127.3 (27) litre during propofol anaesthesia (P < 0.05). This change was accompanied by an increase (P < 0.05) in the free fraction of propranolol from 8.5 (0.7) % in awake to 14.0 (0.7) % in propofol-anaesthetized dogs. The combination of the effects of both drug clearance and protein binding resulted in a 65% decrease in the intrinsic clearance of unbound drug (P < 0.05). In contrast with the effects of propofol on drug distribution, infusion of Intralipid alone in another group of six dogs had no significant effects on drug distribution, protein binding or drug metabolism. We conclude that propofol is a modest inhibitor of drug metabolism, but has major effects on propranolol distribution, possibly by changing plasma protein binding.