QUINIDINE AND DOMPERIDONE INTERACTIONS IN THE RAT EXPERIMENTAL MODEL OF REPEATED ADMINISTRATION

This study has investigated domperidone (DOM) and quinidine (QD) interaction in the Wistar rat experimental model of repeated administration. We used nonconventional administration model consistent with occasional administration method. Difference in administration was related to sequence of domperidone alone or with quinidine dosage. Expected domperidone-quinidine interactions could have its origin both in the ability of quinidine to inhibit P-glycoprotein (P-gp) activity as well as cytochrome P450-mediated metabolism of both compounds. There also were examined kinetics of acetaminophen (PAM) administered (30 mg/kg) with domperidone as an indicator of gastric emptying, showing domperidone prokinetic activity, as well as quinidine anticholinergic activity. Domperidone (30 mg/kg) with PAM and with/without quinidine (25 mg/kg) was administered orally according to the disposition regiment different for six examined rat groups. DOM and PAM concentrations in plasma were assayed by HPLC method. Following changes were observed: domperidone did not modify the duration of the uptake phase of acetaminophen; quinidine prolongs gastric emptying time (as a result of anticholinergic action); quinidine given as the fourth or fifth dose with domperidone promotes growth of its concentration in plasma; analysis of changes in the value of AUC(0-2) at the initial three weeks of experiment suggests intensity of domperidone absorption processes, the following week increase in the value AUC(4-6) suggests inhibition of domperidone hepatic biotransformation and the mechanism of induction of absorption during domperidone administration is different from the absorption - inducing effects of quinidine. Both effects are superimposed and produce large, 2, 3-fold change in domperidone's AUC(0-6).