THE IMPAIRMENT OF LIGNOCAINE CLEARANCE BY PROPRANOLOL - MAJOR CONTRIBUTION FROM ENZYME-INHIBITION

To account for a 40% lowering of the systemic clearance of lignocaine by propranolol [a .beta.-adrenoceptor antagonist] treatment it was proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUC[area under the curve]po of lignocaine by 100-140%. This hypothesis was tested in 6 healthy men who received 200 mg hydrated lignocaine hydrochloride orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 .+-. 58 SD% (P < 0.005); it increased the peak plasma lignocaine concentration by 79 .+-. 50 SD% (P < 0.025); and it prolonged the elimination half-life of lignocaine by 20 .+-. 13 SD% (P < 0.05). Propranolol treatment lowered indocyanine green clearance by 11 .+-. 15 SD%, but this change was not significant statistically. Propranolol apparently lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.