Abstract
The calcium channel blocker diltiazem (DTZ) is widely used alone or in combinationwith other drugs in the treatment of hypertention, angina pectoris and cardiac arrhythmias. Aprindine (AP) is a potent class I antiarrhythmic drug. The combination of antiarrhythmic agents, such as DTZ and AP, is often used when single drug therapy is ineffective or poorly tolerated. We previously reported on the drug interaction between DTZ and AP in beagle dogs and in patients with arrhythmia. DTZ is metabolized mainly in the liver, and the N-demethylated species (MA) is a major metabolite through the cytochrome P-450 isoform CYP3A. In the present study, therefore, we investigated the influence of AP on N-demethylation of DTZ using human liver microsomes.We showed that the N-demethylation of DTZ is inhibited by AP in a dose-dependent manner. Especially, at high concentrations of AP (200μM and 250 μM), the production of MA was reduced to 46.5 ± 5.7% and 31.9 ± 2.1% of the control value, respectively. Lineweaver-Burk plots showed that AP competitivery inhibited the N-demethylation of DTZ in hepatic microsomes with a Km value of 248.7μM.CYP3A is responsible for a major part of AP metabolism in the higher concentration range. This enzyme is present in the liver and the gut wall, therefore the gut wall seems to be an important metabolic site. These results suggested that the mechanism of interaction between DTZ and AP is competitive inhibition and it is dependent on intestinal CYP3A.
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