Flecainide enantiomers

The absolute configurations of flecainide enantiomers have been determined on the basis of CD spectra of the N-chloro derivatives. Thus, (+ )-flecainide has the S-configuration while the antipode is R-(-)-flecainide. The optical rotations of hydrochloride salts were also reported. ... 

There are comparatively few reports concerned with the stereoselective pharmacodynamics and pharmacokinetics of flecainide enantiomers. In vivo studies have revealed equipotency and equiactivity for the two enantiomers in mouse and dog models of arrhythmia. In vitro tests on canine Purkinje fibres have also shown that the enantiomers have comparable electrophysiologic activities. The two enantiomers have also shown similar affinities to a receptor site associated with cardiac sodium channels in isolated rat cardiac myocytes. ... 

Menthyl chloroformate, [17], is commercially available and has been used in several applications. For example, Seeman et al. (72) carried out the preparative chromatographic resolution of nornicotine using [17] as a CDA. The diastereomeric carbamates formed via the reaction of racemic nornicotine with [17] were separated by preparative silica gel LC, and the pure enantiomers of nornicotine were liberated by acid-catalyzed hydrolysis of the carbamates (72). Several reports have described the use of [17] in the enantiospecific determination of drug concentrations in biological fluids thus, the reagent has been used in the analysis of encainide and some of its metabolites (73), flecainide (74), and propranolol (75), and other drugs (76). 

CF3CH20 An example of a lack of stereoselectivity of pharmacological action. The enantiomers of flecainide demonstrates an eudismic ratio... 

The pharmacokinetic patterns of the enantiomers following oral administration in humans appear to be essentially parallel. The plasma R/S ratio seems to range from 0.67-1.44 in different patient populations 3,56,59. stereoselective elimination has been suggested in healthy subjects, which have been classified as poor metabolizers of the sparteine debrisoquine type R-flecainide is predominant in plasma after oral administration of the racemate. The oral AUCs of the enantiomers as well as the elimination half-lives were slightly, but significantly, different. This has been interpreted as being the result of stereoselective hepatic metabolism17. 

Tocainide and mexiletine also show stereoselectivity in their action with the R(—) enantiomers being four and two times, respectively, more potent than their antipodes in sodium channel blocking activity (Table 8). In contrast, there is no stereoselectivity in the main antiarrhythmic action of encainide, flecainide, and propafenone (Table 8). 

The nonrenal pathways of elimination of flecainide may account for about 60% of the administered dose. The major pathway of metabolism of flecainide in humans results in sequential production of meta-O-dealky-lated flecainide (MODE) and meta-O-dealkylated lactam of flecainide (MODLF), both of which may further be conjugated with glucuronide or sulfate (Fig. 6) [110]. It was demonstrated that the metabolism of flecainide (formation of both metabolites) in PMs is impaired when compared with EMs. However, the impairment was stereoselective, in that the metabolism of R(—) enantiomer was inhibited more intensely than that of its antipode [110]. 

For flecainide, the renal clearance of both enantiomers [110,126] appears to exceed the expected value ( 50mL/min) based on the glomernlar filtration rate (120mL/min) and the free fraction of the drng in plasma ( 0.4). Active secretion also plays a role in the excretion of the enantiomers. 

However, it appears that the renal clearances of the enantiomers of flecainide are not stereoselective in both healthy volunteers [110] and patients [126]. 

In contrast to flecainide, the renal clearance values [117,127] of the enantiomers of tocainide are less than the expected value ( lOOmL/min) based on a normal glomerular filtration rate and the drug free fraction (0.85-0.9, Table 2), suggesting involvement of tubular reabsorption for the enantiomers. In agreement with the lack of substantial stereoselectivity in plasma protein binding (Table 2) and the nonstereoselective mechanisms involved in renal excretion of the enantiomers, the renal clearance of S(-l-)-tocainide (50 mL/min/70 kg) is very close to that of R(—)-tocainide (57 mL/min/70 kg) [127]. 

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