Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers

✍ Scribed by Kurt-Jürgen Hoffmann; Lars Renberg; Olle Gyllenhaal

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: English
• Weight: 675 KB
• Volume: 11
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/bdd.2510110404

✦ Synopsis

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 f 20.1 ml min-' and 9.7 f 0.8 h) and (S)-tocainide (110.2 f 10.5 ml min-' and 14.5 f 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 t,,, 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 (1 3 1 vs 97 ml min-').