Inhibition of propranolol metabolism by chlorpromazine.

Abstract

The effects of chlorpromazine 50 mg 8‐hourly on the disposition and effectiveness of propranolol have been investigated in 5 subjects. Propranolol was given orally in a dose of 80 mg 8‐hourly and after 3 days H3‐propranolol was injected intravenously. Both native and H3‐drug were measured in serial blood samples, allowing calculation of intrinsic (oral) clearance and liver blood flow as well as the usual kinetic parameters. The study was repeated after 3 or 4 days of chlorpromazine treatment. Chlorpromazine consistently produced a reduction in intrinsic (oral) clearance from 4.30 ± 0.51 to 2.94 ± 0.16 (p < 0.01), indicative of inhibition of propranolol metabolism. This was associated in an increase in bioavailability from 25 ± 3 to 32 ± 4% (p < 0.005). As would be expected with a highly extracted drug, the change in systemic (intravenous) clearance was much less and was not significant. There were no changes in liver blood flow, volume of distribution, t½, or plasma binding of propranolol. Propranolol efficacy was determined in 3 subjects. In 2 of these plasma levels of propranolol were increased by chlorpromazine at the time of study and resulted in increased isoproterenol antagonism and lowered plasma renin activity. In the third subject plasma propranolol levels were only slightly elevated and no clear pharmacodynamic changes were detected. A sixth subject experienced postural hypotension and syncope following the first dose of chlorpromazine. It was unclear whether this was due to chlorpromazine alone or to an interaction with propranolol. We conclude that chlorpromazine can inhibit the metabolism of propranolol in man, thereby increasing propranolol efficacy.