Metoprolol CYP2D6 substrate

Hamelin, B.A., Bouayad, A., Methot, J., Jobin, J., Desgagnes, P., Poirier, R, Allaire, J., Dumesnil, J., and Turgeon, J. (2000) Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 67 466 77. 

In a more comprehensive study, Madani et al. (165) quantified CYP2D6 protein in 20 human jejunum and 31 human livers. They found that the median microsomal-specific CYP2D6 content was less than 8% of the hepatic microsomal content (0.85 vs. 12.8 pmol/mg) and that there was extensive interindividual variability in protein content for both tissues. These investigators also characterized the catalytic activity of the same jejunal microsomes toward the recognized CYP2D6 substrate metoprolol and found that a-hydroxylation reaction rate was significantly correlated with CYP2D6 protein content (r = 0.75). 

Substrates CYP2D6 Most i-blockers, codeine, clomipramine, clozapine, codeine, encainide, flecainide, fluoxetine, haloperidol, hydrocodone, 4-methoxy-amphetamine, metoprolol, mexiletine, oxycodone, paroxetine, propafenone, propoxyphene, risperidone, selegiline (deprenyl),... 

There is a wide choice of dmgs that are substrates for CYP2D6, but sparteine, debrisoquine, desipramine, dextromethorphan, and metoprolol have been used most frequently, both in vitro and in vivo. One advantage for in vivo drug-drug interaction studies is that most of the substrates were identified in the clinic rather than by the use of a battery of in vitro methods. 

Bisoprolol is eliminated about 50% by renal elimination, whereas metoprolol and carvedilol are essentially completely metabolized and undergo extensive hepatic first-pass metabohsm. Both metoprolol and carvedilol are also substrates for the cytochrome P450 2D6, which is known to be polymorphic. Thus the 7% of the white population and 1 % to 2% of the Asian-American and African-American populations who are CYP2D6 poor metabolizers would be expected to have more pronounced effects than anticipated at the usual doses of carvedilol and metoprolol. 

Not understood. The elinieal pietuie is that of exeessive beta-bloekade, and additive pharmaeodynamie effeets are possible. In addition, amiodar-one inereases the levels of metoprolol via inhibition of the eytoehrome P450 isoenzyme CYP2D6, and this may be signifieant in fast metabolis-ers. See Genetie faetors , (p.4), for more information about fast metabo-lisers. Other beta bloekers that are also substrates of CYP2D6, and whieh eould therefore be similarly affeeted, inelude earvedilol and propranolol. 

---