Pharmacokinetic Implications for the Clinical Use of Propofol

Abstract

Propofol, the recently marketed intravenous induction agent for anaesthesia, is chemically unrelated to earlier anaesthetic drugs. This highly lipophilic agent has a fast onset and short, predictable duration of action due to its rapid penetration of the blood-brain barrier and distribution to the CNS, followed by redistribution to inactive tissue depots such as muscle and fat. On the basis of pharmacokinetic-pharmacodynamic modelling, a mean blood-brain equilibration half-life of only 2.9 minutes has been calculated. In most studies, the blood concentration curve of propofol has been best fitted to a 3-compartment open model, although in some patients only 2 exponential phases can be defined. The first exponential phase half-life of 2 to 3 minutes mirrors the rapid onset of action, the second (34 to 56 minutes) that of the high metabolic clearance, whereas the long third exponential phase half-life of 184 to 480 minutes describes the slow elimination of a small proportion of the drug remaining in poorly perfused tissues. Thus, after both a single intravenous injection and a continuous intravenous infusion, the blood concentrations rapidly decrease below those necessary to maintain sleep (around 1 mg/L), based on both the rapid distribution, redistribution and metabolism during the first and second exponential phases (more than 70% of the drug is eliminated during these 2 phases). During long term intravenous infusions cumulative drug concentrations and effects might be expected, but even then the recovery times do not appear to be much delayed. The liver is probably the main eliminating organ, and renal clearance appears to play little part in the total clearance of propofol. On the other hand, because the total body clearance may exceed liver blood flow, an extrahepatic metabolism or extrarenal elimination (e.g. via the lungs) has been suggested. Approximately 60% of a radiolabelled dose of propofol is excreted in the urine as 1- and 4-glucuronide and 4-sulphate conjugates of 2,6-diisopropyl 1,4-quinol, and the remainder consists of the propofol glucuronide. Thus for hepatic and renal diseases, co-medication, surgical procedure, gender and obesity do not appear to cause clinically significant changes in the pharmacokinetic profile of propofol, but the decrease in the clearance value in the elderly might produce higher concentrations during a long term infusion, with an increased drug effect. In addition, the lower induction dose observed in relation to increased age might be partly explained by a smaller central volume of distribution. Interestingly, the concentration-effect relationship of propofol appears to be much less variable between individuals than are its disposition kinetics. At the onset of unconsciousness mean blood concentration of around 6 to 10 mg/L is needed, but during maintenance of anaesthesia much lower levels of around 2 to 4 mg/L are effective. A good correlation between EEG activity and blood propofol concentrations has been reported. Importantly, a clear hysteresis in concentration-effect studies has been found with higher blood propofol concentrations at the onset of unconsciousness than are necessary to maintain sleep. Propofol has a unique pharmacokinetic profile, a knowledge of which may improve the understanding of its pharmacodynamic properties. Despite a very long terminal half-life related to a high volume of distribution, recovery from propofol is short and predictable due to the relative importance of distribution rates and elimination. Moreover, the good concentration-effect relationship with a low individual variability is of great clinical significance. © 1989, ADIS Press Limited. All rights reserved.