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Tocainide : E.C.D.-G.L.C. analysis, pharmacokinetics and drug interactions

University of British Columbia

Tocainide, a structural analog of lidocaine is an orally effective antiarrhythmic agent. From the structure it can be postulated that tocainide will undergo metabolism, primarily by oxidative processes. Microsomal enzyme systems responsible for such oxidative processes have been shown to be induced or inhibited by a number of factors. The disposition of a number of antiarrhythmic agents has been shown to be influenced by co-administered drugs. The major objective of this study was to investigate the susceptibility of tocainide to enzyme inducing and inhibiting agents. An electron capture detector gas chromatographic method involving the formation of a monoheptafluorobutyryl derivative of tocainide was developed for the analysis of tocainide in biological fluids. The minimum detectable level of tocainide was 50 pcg and the standard curve obtained was linear over a range of 100 pcg to 3 ng. The elimination kinetics of tocainide was found to be non-linear over the dosage range studied. The area under the plasma concentration versus time curve increased in a disproportionate manner with an increase in the dose administered. A greater than 100% increase in the dose excreted as the intact tocainide in urine suggested that the dose dependency of tocainide elimination is due to saturable metabolism. Following administration of tocainide (15 mg/kg) to rats, 15-20% of the dose was excreted as the intact drug. An additional 20% of the dose was excreted as the acid hydrolysable conjugates of tocainide. This is an under estimation of the total amount of the conjugates present, as later studies revealed instability of tocainide under the conditions used for acid hydrolysis. Hydrolysis with β-glucuronidase showed approximately 40% of the conjugate to be a glucuronide conjugate. The enzyme hydrolysis mediated by β-glucuronidase was blocked by its specific inhibitor 1:4 saccharo-lactone. During gas chromatography-mass spectrometry studies of the urine, a deaminated tocainide, dimethyl aniline (xylidine) and a cyclic hydantoin derivative of tocainide were also observed to be present as metabolites in rat urine. A multiple analytical scheme developed,confirmed that a cyclic hydantoin derivative of tocainide which was reported to be a "metabonate" in man, was present as a metabolite in rats. Pretreatment of the rats with phenobarbital (70 mg/kg for seven days) markedly reduced the half-life of tocainide (20 mg/kg) by twofold. This was due to an induction of the metabolism of tocainide, as shown by a significant reduction in the percent of dose excreted as intact tocainide in rats. The extent of induction was more pronounced following oral administration of tocainide as compared to an intravenous administration of tocainide. The reduction in the percent of dose excreted as the acid hydro-lysable conjugate suggested that pathways other than conjugating systems are probably induced to a greater extent than conjugating systems. SKF 525-A (50 mg/kg administered 40 minutes prior to tocainide) pretreatment markedly prolonged the half-life of tocainide (15 mg/kg). The inhibition of tocainide metabolism by SKF 525-A was reflected in terms of the increase in the percent of dose excreted as intact tocainide. The extent of inhibition of the metabolism was greater following a 15 rng/kg dose-as compared to a 20 mg/kg dose. This observation supports the existence of a saturable metabolic pathway for the elimination of tocainide in rats. Experiments were carried out to determine the effect of a; competitive inhibitor of glucuronide conjugating pathways on the elimination of tocainide. The observation of an increased excretion of the percent of dose as the intact tocainide suggests competitive inhibition of tocainide metabolism. However, the extent of inhibition was found to depend upon the route of administration as well as the pretreatment schedule used. Since in humans, glucuronide conjugation accounts for a greater percent of the dose administered, salicylamide would be expected to have a more pronounced effect on tocainide metabolism in human. It can be concluded that the disposition of tocainide is susceptible to both enzyme inducing and enzyme inhibiting agents in rats. The results obtained in the present study points to the necessity for carrying out similar experiments in humans so that the patients could obtain maximum benefits of tocainide therapy. Further more, caution should be exercised in interpreting results when nonphysiological solvents are used to administer poorly soluble drugs.

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2010-03-15

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http://hdl.handle.net/2429/21923

Pharmaceutical Sciences

University of British Columbia

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