ANALYSIS AND STEREOSELECTIVE METABOLISM AFTER SEPARATE ORAL DOSES OF TOCAINIDE ENANTIOMERS TO HEALTHY-VOLUNTEERS

The potential of stereoselective metabolism of tocainide was studied in six healthy volunteers after separate oral administration of the pure enantiomers in solution. A method was developed to convert the N‐carbamoylglucuronide of tocainide in plasma and urine by base treatment to a hydantoin derivative which after extraction and silylation was analysed by selected ion monitoring using a deuterated internal standard. Analytical problems concerning side‐reactions during derivatization of the conjugate are discussed. The peak plasma levels of the enantiomers, observed at ≦2 h after dosing, were similar but plasma clearances and terminal half‐lives were different after oral administration of (R)‐tocainide (195.5 ± 20.1 ml min−1 and 9.7 ± 0.8 h) and (S)‐tocainide (110.2 ± 10.5 ml min−1 and 14.5 ± 1.7 h). Over 0–96 h the averaged urinary recovery of (R)‐tocainide was 36 per cent and of (S)‐tocainide 50 per cent. Stereoselective metabolism was a likely mechanism for the observed differences as the urinary recovery of the conjugate formed from (R)‐tocainide differed substantially from that of (S)‐tocainide (45 vs 1.2 per cent of given dose). Plasma t1/2 of the (R)‐ and (S)‐conjugate were 9.9 and 18.7 h, respectively, indicating formation rate limited kinetics of the metabolite. The renal clearances of the conjugates were not significantly different (131 vs 97 ml min−1). Copyright © 1990 John Wiley & Sons, Ltd.