EFFECTS OF PROPOFOL ON HUMAN HEPATIC-MICROSOMAL CYTOCHROME-P450 ACTIVITIES

1. The potential of propofol to inhibit the activity of major human cy tochrome P450 enzymes has been examined in vitro using human liver mic rosomes. Propofol produced inhibition of CYP1A2 (phenacetin O-deethyla tion), CYP2C9 (tolbutamide 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation) and CYP3A4 (testosterone 6 beta-hydroxylation) activ ities with IC50 = 40, 49, 213 and 32 mu M respectively. K-1 for propof ol against all of these enzymes with the exception of CYP2D6, where pr opofol showed little inhibitory activity, was 30, 30 and 19 mu M respe ctively for CYPs 1A2, 2C9 and 3A4. 2. Furafylline, sulphaphenazole, qu inidine and ketoconazole, known selective inhibitors of CYPs 1A2, 2C9, 2D6 and 3A4 respectively, were much more potent than propofol having IC50 = 0.8, 0.5, 0.2 and 0.1 mu M; furafylline and sulphaphenazole yie lded K-1 = 0.6 and 0.7 mu M respectively. 3. The therapeutic blood con centration of propofol (20 mu M; 3-4 mu g/ml) together with the in vit ro K-1 estimates for each of the major human P450 enzymes have been us ed to estimate the extent of cytochrome P450 inhibition, which may be produced in vivo by propofol. This in vitro-in vivo extrapolation indi cates that the degree of inhibition of CYP1A2, 2C9 and 3A4 activity wh ich could theoretically be produced in vivo by propofol is relatively low (40-51%); this is considered unlikely to have any pronounced clini cal significance. 4. Although propofol has now been used in > 190 mill ion people since its launch in 1986, there are only single reports of possible drug interactions between propofol and either alfentanil or w arfarin. Consequently, it is difficult to conclude from either the pub lished literature or the ZENECA safety database whether there is any e vidence to indicate that propofol produces clinically significant drug interactions through inhibition of cytochrome P450-related drug metab olism.