Interaction between oral hydralazine and propranolol. I. Changes in absorption, presystemic clearance and splanchnic blood flow

Abstract

A study was undertaken of propranolol pharmacokinetics in dogs before and after oral coadministration of hydralazine to determine whether interactions described in humans could be reproduced in an animal model. Additionally, physiological parameters considered to be relevant to the pharmacokinetic handling (absorption rate and splanchnic hemodynamics) were studied. Coadministration of oral hydralazine and propranolol in conscious dogs caused an increase in peak plasma concentration ( Cpmax ) and area under the oral plasma concentration-time curve (AUC) of propranolol ( Cpmax = 19.2 +/- 5.8 ng/ml, control; Cpmax = 91.5 +/- 12.8 ng/ml, posthydralazine : AUC = 65.7 +/- 14.6 ng X hr/ml, control; AUC = 152.4 +/- 23.9 ng X hr/ml, posthydralazine : mean +/- S.E.M., n = 5; P less than .01 and P less than .01), without change either in the peak plasma level, time to peak or plasma AUC of [14C] propranolol and metabolites (P greater than .70, P greater than .90 and P greater than .60, respectively) or in urinary recovery (urinary recovery = 39.7 +/- 4.3% dose, control; urinary recovery = 41.8 +/- 6.2% dose, posthydralazine ). When propranolol was administered i.v., hydralazine caused a small (42.3 +/- 18%), but significant (P less than .025), increase in systemic clearance. Oral bioavailability increased from 7.3 +/- 2.1 to 23.6 +/- 5.1% (mean +/- S.E.M., n = 5, P less than .025), hepatic extraction showed correspondingly inverse changes and estimated hepatic blood flow increased from 34.9 +/- 3.8 to 63.3 +/- 10.8 ml/min/kg (P less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)