Stereoselective pharmacokinetics of tocainide in human uraemic patients and in healthy subjects

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Abstract
The disposition of tocainide enantiomers were examined in healthy human subjects and uraemic patients following a single i. v. dose (200 mg) of racemic tocainide hydrochloride. In the healthy subjects, the total body clearance of R(−)-tocainide was significantly greater than that of S(+)-tocainide (2.62 vs 1.70 ml·min−1·kg−1). Renal clearance also favoured R(−)-tocainide and appeared to contribute significantly to the stereoselective total body clearance. The volume of distribution of the enantiomers did not differ significantly. Uraemia produced a marked decrease in the total body clearance with no apparent effect on the volume of distribution of both enantiomers. The S/R ratio for total body clearance decreased significantly from 0.66 in healthy subjects to 0.54 in the uraemics, while the ratio for terminal elimination half-life significantly increased from 1.43 to 1.59. These results indicate that uraemia alters the degree of stereoselectivity in the pharmacokinetic parameters of tocainide enantiomers.