Cytochrome P450 enzymes blockers

Bufuralol (11) is a p-adrcnoccptor agent (beta-blocker), developed by Roche [8,9], As part of a continuing program on the synthesis of substrates and metabolites for Cytochrome P450 studies, we wished to prepare both optically active bufuralol and an important metabolite, the hydroxybufuralol (12). This brief account of our efforts illustrates the way in which classical resolution is giving way to asymmetric synthesis, whether mediated by synthetic chiral auxiliaries, conventional catalysts, or enzymes. 

The concurrent use of beta blockers and digoxin during clinical trials is reported not to affect the safety or efficacy of ibutilide. Ibutilide is said not to affect the cytochrome P450 isoenzymes CYP3A4 or CYP2D6 and so metabolic interactions with drugs affected by these enzymes would not be expected. Study is needed to confirm all ofthese predictions and findings. 

Calcium-channel blockers also undergo interactions due to altered metabolism. Both verapamil and diltiazem are principally metabolised by the cytochrome P450 isoenzyme CYP3A4, and also inhibit this enzyme (see Table 1.4, (p.6)). They are therefore affected by drugs that induce or inhibit CYP3A4, and also themselves interact with drugs metabolised by CYP3A4. 

It appears that St John s wort decreased the bioavailability of bothii- and 5-verapamil by inducing their metabolism by the cytochrome P450 isoenzyme CYP3A4 in the gut. An effect on P-glycoprotein-mediated transport is not likely, as intestinal permeability was not significantly altered. The clinical importance of this interaction is not known but it may be prudent to avoid concurrent use. There appears to be no information about other calcium-channel blockers, but as they are also affected by other CYP3A4 enzyme inducers, it would seem prudent to monitor concurrent use carefully. More study is required. 

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