INTERACTION BETWEEN ORAL HYDRALAZINE AND PROPRANOLOL .1. CHANGES IN ABSORPTION, PRESYSTEMIC CLEARANCE AND SPLANCHNIC BLOOD-FLOW

  • 1 January 1984
    • journal article
    • research article
    • Vol. 229  (2) , 509-514
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. Physiological parameters considered 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 .cntdot. h/ml, control; AUC = 152.4 .+-. 23.9 ng .cntdot. h/ml, posthydralazine: mean n = 5; P < 0.01 and P < 0.01), without change either in the peak plasma level, time to peak or plasma AUC of [14C] propranolol and metabolites (P > 0.70, P > 0.90 and P > 0.60, 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 < 0.025), increase in systemic clearance. Oral bioavailability increased from 7.3 .+-. 2.1 to 23.6 .+-. 5.1% (mean, n = 5, P < 0.025), hepatic extraction showed correspondingly inverse changes and estimated hepatic blood flow increased from 34.9 .+-. 3.8 to 63.3 .+-. 10.8 ml/min per kg (P < 0.025). Administration of hydralazine into the jejunum of anesthetized dogs produced significant increases in both mesenteric artery flow (QMA) and hepatic artery flow (QHA), with a threshold dose of 1.25-2.5 mg and maximum effects at a cumulative dose of 5-15 mg. Maximal flow changes above control (25-mg dose) to hydralazine were 130 .+-. 18% control (QMA) and 66 .+-. 10% control (QHA) (QMA = 249 .+-. 22.1 ml/min control, QMA 559 .+-. 44 ml/min posthydralazine; QHA = 174 .+-. 19.5 ml/min, control; QHA = 280 .+-. 38 ml/min, posthydralazine). The interaction between oral hydralazine and propranolol in dog is more marked than in humans, but there are qualitative parallels in patterns of absorption and clearance, indicating that hydralazine produces a major change in 1st-pass hepatic clearance in both instances. Parallels in splanchnic vascular reactivity to hydralazine are confirmed. Apparently, the dog is a relevant animal in which to study mechanisms determining oral availability and presystemic interactions of high clearance drugs.