INHIBITION OF CYP2D6 ACTIVITY BY TREATMENT WITH PROPRANOLOL AND THE ROLE OF 4-HYDROXY PROPRANOLOL

1 The 4-hydroxylation of propranolol by rat and human liver microsomes is associated with formation of a chemically reactive species which b inds irreversibly to cytochrome P4502D6 (CYP2D6) destroying its cataly tic function. Therefore, the effect of propranolol treatment (80 mg tw ice daily) on debrisoquine phenotype was examined, to see if it result ed in phenocopying in vivo. The role of 4-hydroxypropranolol (4OHP) in the inhibition of CYP2D6 activity was also studied using microsomes f rom yeast expressing CYP2D6 and from human livers; metoprolol was used as the CYP2D6 substrate. 2 Although a significant effect on apparent oxidation phenotype was demonstrated, the absolute change in the urina ry debrisoquine/4-hydroxydebrisoquine ratio (D/4HD) was small, such th at no extensive metaboliser who received propranolol treatment was rec lassified as a poor metaboliser. The in vitro studies indicated that 4 OHP is a potent inhibitor of metoprolol metabolism (K-i similar to 1 m u M). This inhibitory effect was enhanced when 40HP was pre-incubated in the presence of a NADPH generating system and human liver microsome s. The effect was decreased significantly when reduced glutathione was added to the pre-incubation mixture. Metabolism of 4OHP occurred when incubated with human liver microsomes in the presence of a NADPH gene rating system and irrespective of CYP2D6 phenotype; yeast expressing C YP2D6 did not metabolise 4OHP. 3 We conclude that, although treatment with propranolol 80 mg twice daily significantly decreases the catalyt ic function of CYP2D6, the inhibition is insufficient to result in phe nocopying. The reactive intermediate produced by further metabolism of 4OHP is probably scavenged effectively in vivo by glutathione and oth er nucleophiles.