Stereoselective disposition of RS-tocainide in man
- 8 Downloads
- 16 Citations
Summary
The disposition of RS-tocainide in three healthy volunteers has been studied after oral administration of a pseudoracemic mixture containing S( + ) [3H] tocainide as a radioactive tracer together with a therapeutic dose of the racemate. Analytical methods based on HPLC have been developed to measure S( + ) and R(−) tocainide in urine samples. Selected ion detection has been used for quantification of a tocainide conjugate. The radioactive dose was efficiently absorbed and mainly cleared via the kidneys. The elimination halflife of RS-tocainide was found to be 14.3 hours. The elimination half-lives of the two stereoisomers of tocainide differed significantly, i.e. R(−) tocainide 10 hours, and S( + ) tocainide 16.7 hours. The observed t1/2 for the tocainide conjugate of 10.3 hours was close to that of R(−) tocainide, indicating that the metabolite was preferably formed from the R(−) stereoisomer of tocainide. Of the given dose, between 45 and 70% can be accounted for.
Key words
Tocainide stereoselective metabolism radioisotopes HPLC and GC/MSPreview
Unable to display preview. Download preview PDF.
References
- 1.Swedberg K., Pehrson J. and Rydén L. (1978): Eur. J. Clin. Pharmacol., Electrocardiographic and hemodynamic effects of tocainide (W-36095) in man,14, 15–19.CrossRefPubMedGoogle Scholar
- 2.Ryan W., Engler R., LeWinter M. and Karliner J.S. (1979): Am. J. Cardiol., Efficacy of a new oral agent (tocainide) in the acute treatment of refractory ventricular arrhythmias,43, 285–291.CrossRefPubMedGoogle Scholar
- 3.Graffner C, Conradson T.B., Hofvendahl S. and Rydén L. (1980): Clin. Pharmacol. Ther., Pharmacokinetics of tocainide following intravenous and oral administration in healthy subjects and in patients with acute myocardial infarction,27, 64–71.PubMedGoogle Scholar
- 4.Lalka D., Meyer M.B., Duce B.R. and Elvin A.T. (1976): Clin. Pharmacol. Ther., Kinetics of the oral antiarrythmic lidocaine congener, tocainide,19, 757–766.PubMedGoogle Scholar
- 5.Elvin A.T., Keenaghan J.B., Byrnes E.W., Tenthorey P.A., McMaster P.D., Takman B.H., Lalka D., Manion C.V., Baer D.T., Wolshin E.M., Meyer M.B. and Ronfeld R.A. (1980): J. Pharm. Sei., Tocainide conjugation in humans: novel biotransformation pathway for a primary amine,69, 47–49.CrossRefGoogle Scholar
- 6.Gipple K.J., Chan K.T., Elvin A.T., Lalka D. and Axelson J.E. (1982): J. Pharm. Sei., Species differences in the urinary excretion of the novel primary amine conjugate : tocainide carbamoyl O-β-D-glucuronide,71, 1011–1014.CrossRefGoogle Scholar
- 7.Venkataramanan R., Abbott F.S. and Axelson J.E. (1982): J. Pharm. Sei., Metabolism of tocainide in the rat,71, 491–494.CrossRefGoogle Scholar
- 8.Venkataramanan R. and Axelson J.E. (1981): Xenobiotica, 3-(2,6-Xylyl)-5-methylhydantoin — a metabolite or a metabonate of tocainide in rats?,11, 259–265.CrossRefPubMedGoogle Scholar
- 9.Gal J., French T.A., Zysset T. and Haroldsen P.E. (1982): Drug Metab. Disp., Disposition of (R.S)-tocainide, some stereoselective aspects,10, 399–404.Google Scholar
- 10.Lagerström P.-O. and Persson B.-A. (1978): J. Chromatogr., Liquid chromatography in the monitoring of plasma levels of antiarrhythmic drugs,149, 331–340.CrossRefPubMedGoogle Scholar
- 11.Erickson M., personal communication.Google Scholar
- 12.Bäärnhielm C, unpublished observations.Google Scholar
- 13.Ronfeld R.A., Wolshin E.M. and Block A.J. (1982): Clin. Pharmacol. Ther., On the kinetics and dynamics of tocainide and its metabolites,31, 384–392.PubMedGoogle Scholar
- 14.Cone E.J., Buchwald W.F. and Darwin W.D. (1982): Drug Metab. Dispos., Analytical controls in drug metabolic studies. II. Artifact Formation During Chloroform Extraction of Drugs and Metabolites with Amine Substituents,10, 561–567.PubMedGoogle Scholar
- 15.Evans E.A. (1966): Tritium and its Compounds, Butterworths, London.Google Scholar