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Stereoselective assay of tocainide enantiomers and study of their selective disposition in man Pillai, Gopalakrishna


Tocainide, a structural analog of lidocaine, is an orally effective antiarrhythmic agent. The chemical structure of tocainide includes an asymmetric center and the drug is used clinically in the racemic form. Although the antiarrhythmic properties of the tocainide enantiomers have not been studied in man, the R(-) enantiomer is three times more potent than the S(+) isomer as an antiarrhythmic agent in a mouse model. Pharmacokinetic studies of enantiomers can reveal whether the stereoselectivity lies in the process of absorption, distribution, metabolism or a combination of these processes. In order to study their disposition a very sensitive and selective analytical technique is required that is capable of resolving the two isomers when present together in biological fluids. The main objective of this study was to develop such a method and to apply it for the simultaneous measurement of tocainide enantiomers in human plasma, urine and saliva and to examine their stereoselective disposition. A gas chromatographic method using a fused-silica capillary column coated with a chiral stationary phase (Chirasil-Val®) was developed for the direct resolution of tocainide enantiomers. Base-line resolution of their heptafluorobutyryl derivatives was achieved and no interfering peaks were observed in plasma, urine or saliva extracts. The identity of the resolved peaks was established by comparison of the retention time, optical rotation and mass spectra of tocainide enantiomers, which were obtained by a stereospecific synthesis. In order to study stereoselective disposition, 200 mg of (±) tocainide hydrochloride (tablets) were given orally to seven healthy male subjects and by intravenous infusion to five of them. Blood (8 mL) was withdrawn at predetermined time intervals up to 72 hours and urine was collected up to 96 hours following drug administration. Saliva (2 mL) samples were also collected at the time of blood collection. Calibration curve data and precision of assay of plasma, urine and saliva were determined by triplicate analyses of six concentrations ranging from 50 ng to 3000 ng of (±) tocainide hydrochloride along with 1000 ng of 1-aminoacetoxylidide (W-49167) as the internal standard. The relative standard deviations were in the range of 4 to 9.9% for plasma, 2.6 to 7.2% for urine and 2.1 to 5.9% for saliva. The lowest concentration that could be determined by the split mode of injection was 25 ng of each enantiomer per mL of plasma. The plasma concentration-time data were analysed by a computer program (AUTOAN and NONLIN) and were found to fit a two compartment model. The half-lives calculated from the plasma data, following an oral dose, were 16.3 ±4 hours for the dextro-isomer and 11.9 ± 2.7 hours for the levo-isomer. The corresponding half-lives following an intravenous dose were 17.0 ± 2.5 hours and 11.7 ± 2.4 hours respectively. The plasma clearances were 144 ± 28 mL/min and 222 ± 54 mL/min for the dextro- and levo-isomers, respectively. The volumes of distribution, (V[sub d])β, were 2.47 ± 0.43 L/Kg and 2.52 ± 0.49 L/Kg for the dextro- and levo-isomers respectively. Following oral administration, both isomers were absorbed rapidly at the same rate and peak levels were reached at the same time. The area under the plasma concentration-time curve following oral dose was higher than that following intravenous administration and therefore the bioavailability was 151 ± 43% for the dextro- isomer and 167 ± 67% for the levo-isomer. Bioavailability calculated from urine data was 109 ± 18% for the dextro-isomer and 112 ± 29% for the levo-isomer. The mean enantiomer ratio, (+) tocainide/(-) tocainide, in the plasma was 1.52 at 24 hours and 1.88 at 48 hours following an oral dose of the racemate. Similar enantiomer ratios were observed in the urine but enantiomer composition in the saliva was different in that the levo-isomer level was higher than the dextro- isomer and that the levels of both the isomers were higher than the corresponding plasma concentrations. The saliva/plasma concentration ratio was 2.06 ± 0.50 for the dextro-isomer and 3.68 ± 0.76 for the levo-isomer. The correlation between saliva and plasma concentration, ranged from, r = 0.910 to 0.987 for the dextro-isomer and r = 0.884 to 0.986 for the levo-isomer. Tocainide enantiomer disposition was also studied in a patient with renal dysfunction (serum creatinine = 13.8 mg%). The half-life of the dextro-isomer was 45 hours and that of the levo-isomer was 28.7 hours, which corresponded to a 2.5 fold increase as compared to healthy subjects. The plasma clearance was 86 mL/min and 146 mL/min for the dextro- and levo-isomers, respectively. During hemodialysis, the half-life was decreased to 6.5 hours and 5.4 hours for the dextro- and levo-isomers, respectively. Thus it can be concluded that the disposition of tocainide enantiomers in the human is stereoselective and that the enantiomer ratio in the plasma is variable between subjects.

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