Studies on the Drug Interaction of Diltiazem. III. Mechanism of the Absorption Enhancing Effect of Diltiazem on the Co-administrated Propranolol

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Abstract
Absorption enhancing mechanism on propranolol by diltiazem was investigated in dog. No competition of plasma protein binding between the 2 drugs was observed in equilibrium dialysis. When these drugs were i.v. administered in a combined injection, there was no alteration in the elimination behaviors. There occurs no substantial interaction between diltiazem and propranolol in the systemic circulation. In vitro metabolism study using liver homogenate revealed mutual inhibition of metabolism of propranolol and diltiazem, but the inhibitor constant (ki) was much higher than the plasma concentration. In vivo experiments showed that hepatic blood flow was increased substantially by i.v. and intraduodenal administration of diltiazem in anesthetized dogs. This pharmacological action apparently causes reduction of the first pass metabolism of propranolol in the liver. Similar effects to enhance the absorption of propranolol observed by coadministration of vasodilators other than diltiazem, support the above idea. The relationship between absolute availability of propranolol in individual dogs and the promoting effect of diltiazem on combined administration was significant. Diltiazem evidently enhanced the systemic availability of propranolol mainly by increasing hepatic blood flow.

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