Effect of I.V. Anaesthesia With Propofol on Drug Distribution and Metabolism in the Dog

Abstract

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.

Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats

“…, ), administration of the two drugs together can be expected to slow elimination and increase plasma drug concentrations (Perry et al. ), altering the pharmacokinetics of both agents. There are several reports of benzyl alcohol toxicity in cats due to administration of substances containing this preservative (Bedford & Clarke , ; Humphreys ; Cullison et al.…”

A model to study intestinal and hepatic metabolism of propranolol in the dog

“…It is therefore feasible to apply this model during an exploratory laparotomy to assess liver function when extensive cirrhosis or neoplastic metastasis is found, particularly following substantial hepatic resection. As a range of conditions are known to affect hepatic drug metabolism, including anaesthetic agents used to perform surgery (Perry et al. , 1991), it is also a useful experimental model to specifically investigate drug extraction and metabolism by the liver.…”

“…In conclusion, the model presented in this study may be a useful tool to study a range of conditions that are known to affect hepatic drug metabolism, including anaesthetic agents used prior to performing surgery (Perry et al. , 1991).…”

Propofol inhibits renal cytochrone P450 activity and enflurance defluorinationin vitro in hamsters

“…9,10 Propofol interacts with drugs such as propranolol, by changing plasma protein binding and affecting its drug disposition. 11 The enzymatic degradation of sufentanil and alfentanil in the liver may be inhibited by propofol. 1 2 Previous investigations in the rat and in our human liver model demonstrated that interference in oxidative metabolism by propofol was mainly through inhibition of the cytochrome P450-dependent monooxygenase system.…”