The investigation was undertaken to observe the effects of alteration of liver blood flow and of liver metabolism on the kinetics of two antiarrhythmic drugs, lignocaine, a highly hepatic cleared drug and tocainide, a drug with low hepatic clearance in intact rats. An initial study was undertaken to investigate the basic kinetics of both drugs following oral and intravenous administration at different dosage levels. Lignocaine was found to be the subject of "first pass" effect with a systemic availability of 0.019. Tocainide was found to be approximately 80% eliminated by the liver and approximately 20% by the kidneys. Systemic availability of tocainide was 0.94. The t1/2 of lignocaine was found to be the same after intravenous and oral administration. The t1/2 of tocainide was found to be longer after oral than intravnous administration. From this preliminary work the dose range in which the kinetics of lignocaine and tocainide showed first order kinetics was established. Doses within this range were chosen for the study of the effects of alterations of liver blood flow and liver enzyme activity on the kinetics of both drugs. Two enzyme inducing agents were used, 3,4 benzpyrene which induces hepatic enzymes without altering liver blood flow and phenobarbitone which induces hepatic enzymes and increases hepatic blood flow. Sotalol, a ?-adrenoceptor antagonist was found to decrease cardiac output and liver blood flow. Liver blood flow was measured by the radioactively labelled microsphere method. By this method flow to other organs and fractional distribution of cardiac output can also be observed. Changes in kinetics of lignocaine and tocainide at selected doses after intravenous and oral administration were observed in rats treated with either, 3,4 benzpyrene, phenobarbitone or sotalol. The results were compared with those obtained from the two mathematical models, the "well-stirred" and the "parallel tube" models which predict change in kinetics when these major determinants of hepatic drug elimination, blood flow and metabolism are changed. For tocainide, a metabolism dependent drug, both models gave a satisfactory prediction of changes in hepatic extraction ratio, systemic availability and AUC when blood flow and metabolism are altered. Reasonably close prediction of kinetic changes of lignocaine a high hepatic clearance drug is obtained when hepatic enzymes are induced. For changes in liver blood flow with lignocaine the predictions for hepatic extraction ratio and AUCi.v. are close to the observed values but those for AUCp.o. were not with both models.
|Date of Award||1980|