Impact of stereoselectivity on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs.

Many antiarrhythmic drugs introduced into the market during the past three decades have a chiral centre in their structure and are marketed as racemates. Most of these agents, including disopyramide, encainide, flecainide, mexiletine, propafenone and tocainide, belong to class I antiarrhythmics, whereas verapamil is a class IV antiarrhythmic agent. Except for encainide and flecainide, there is substantial stereoselectivity in one or more of the pharmacological actions of chiral antiarrhythmics, with the activity of enantiomers differing by as much as 100-fold or more for some of these drugs. The absorption of chiral antiarrhythmics appears to be nonstereoselective. However, their distribution, metabolism and renal excretion usually favour one enantiomer versus the other. In terms of distribution, plasma protein binding is stereoselective for most of these drugs, resulting in up to two-fold differences between the enantiomers in their unbound fractions in plasma and volume of distribution. For disopyramide, stereoselective plasma protein binding is further complicated by nonlinearity in the binding at therapeutic concentrations. Hepatic metabolism plays a significant role in the elimination of these antiarrhythmics, accounting for >90% of the elimination of mexiletine, propafenone and verapamil. Additionally, in most cases, significant stereoselectivity is observed in different pathways of metabolism of these drugs. For some drugs, such as propafenone and verapamil, the stereoselectivity in metabolism is further complicated by nonlinearity in one or more of the metabolic pathways. Further, the metabolism of a number of chiral antiarrhythmics, such as mexiletine, propafenone, encainide and flecainide, cosegregates with debrisoquine/sparteine hydroxylation phenotype. Therefore, it is not surprising that a wide interindividual variability exists in the metabolism of these drugs. Excretion of the unchanged enantiomers in urine is an important pathway for the elimination of disopyramide, flecainide and tocainide. The renal clearances of both disopyramide and flecainide exceed the filtration rate for these drugs, suggesting the involvement of active tubular secretion. However, the stereoselectivity in the renal clearance of these drugs, if any, is minimal. Similarly, there is no stereoselectivity in the renal clearance of tocainide, a drug that undergoes tubular reabsorption in addition to glomerular filtration. Overall, substantial stereoselectivity has been observed in both the pharmacokinetics and pharmacodynamics of chiral antiarrhythmic agents. Because the effects of these drugs are related to their plasma concentrations, this information is of special clinical relevance.