Absorption enhancing mechanism on propranolol by diltiazem was investigated in dog. No competition of plasma protein binding between two drugs was observed in equilibrium dialysis. When these drugs were intravenously administered in a combined injection, there was no alteration in the elimination behaviors. These results show that 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 (k1) was much higher than the plasma concentration. In vivo experiments showed that hepatic blood flow was increased substantially by intravenous and intraduodenal administration of diltiazem in anesthetized dogs. It seems that this pharmacological action 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. Relationship between absolute availability of propranolol in individual dogs and promoting effect of diltiazem on combined administration was significant. On the basis of these findings, it is considered that diltiazem enhanced the systemic availability of propranolol mainly by increasing hepatic blood flow.
