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 less than 0.05) but no significant difference in systemic clearance or hepatic plasma flow. Propofol produced marked changes in drug distribution; volume of distribution (Vss) of propranolol increased 54% from 82.5 (SEM 7.3) litre awake to 127.3 (27) litre during propofol anaesthesia (P less than 0.05). This change was accompanied by an increase (P less than 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 less than 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.

The elderly are more resistant to the effects of propranolol than the young. To determine whether the decreased sensitivity in the elderly could be due to stereoselective alteration in propranolol metabolism, we investigated the effect of age on the oral clearance of (-)-and (+)-propranolol. Six young (aged 24-32, mean 27.3 ± 1.3 years) and six elderly (65-80, mean 71.3 ± 2.7 years) white male volunteers were given a single 80 mg oral dose of racemic propranolol. The mean peak plasma concentrations of both (+)-and (-)-propranolol were significantly higher (P < 0.05) in the elderly (105.7 ± 19.7 and 165.0 ± 29.7 nmol l-1) compared with the young subjects (68.6 ± 10.1 and 115.7 ± 18.1 nmol 1-1). The oral clearances of both (+)-and (-)-propranolol were significantly higher (P < 0.05) in the young (6933 ± 598 and 4554 ± 372 ml min-') than in the elderly (4548 ± 712 and 2941 ± 473 ml min-'). Age had no effect on the relative concentration of the two isomers. Thus, the ratio of (+)-propranolol to (-)-propranolol was 0.67 ± 0.05 in the young compared with 0.65 ± 0.02 in the elderly.

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