title: Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers.
abstract: 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 silation 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 less than or equal to 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).
authors.affiliation: AB Hässle Cardiovascular Research Laboratories, Mölndal, Sweden.
authors.forename: K J
authors.initials: KJ
authors.lastname: Hoffmann
authors.forename: L
authors.initials: L
authors.lastname: Renberg
authors.forename: O
authors.initials: O
authors.lastname: Gyllenhaal
mesh_terms: D000328:Adult; D001711:Biotransformation; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D013237:Stereoisomerism; D016677:Tocainide
chemical_list: D016677:Tocainide; D008012:Lidocaine