Carvedilol and metoprolol are two of the most commonly prescribed -blockers in cardiovascular medicine
and primarily used in the treatment of hypertension and heart failure. Cytochrome P450 2D6 (CYP2D6) is the
predominant metabolizing enzyme of these two drugs. Since the first description of a CYP2D6 sparteinedebrisoquine
polymorphism in the mid-seventies, substantial genetic heterogeneity has been reported in the human
CYP2D6 gene, with ~100 different polymorphisms identified to date. Some of these polymorphisms render the enzyme
completely inactive while others do not modify its activity. Based on all the identified variants, four metabolizer
phenotypes are nowadays used to characterize drug metabolism via CYP2D6 in humans: ultra-rapid metabolizer
(UM); extensive metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM) phenotypes.
As a consequence of these CYP2D6 metabolizer phenotypes, pharmacokinetics and bioavailability of carvedilol
and metoprolol can range from therapeutically ineffective levels (in the UM patients) to excessive (overdose) and potentially toxic concentrations
(in PM patients). This, in turn, can result in elevated risks for either treatment failure (in terms of blood pressure reduction of
hypertensive patients and of improving survival and cardiovascular function of heart failure patients) or for adverse effects (e.g. hypotension
and bradycardia). The present review will discuss the impact of these CYP2D6 genetic polymorphisms on the therapeutic responses
of cardiovascular patients treated with either of these two -blockers. In addition, the potential advantages and disadvantages of implementing
CYP2D6 genetic testing in the clinic to guide/personalize therapy with these two drugs will be discussed.
Keywords: Cardiovascular patient, carvedilol, CYP2D6, genetic testing, heart failure, metoprolol, pharmacogenetics, phenotyping.
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