Diabetes mellitus aggravates ranolazine-induced ECG changes in rats.

Abstract

Diabetes mellitus (DM) is known to affect the pharmacokinetics of drugs. In this study, we evaluated the effect of DM on the liver content of CYP 3A2 enzyme. We also explored the ECG changes after administration of ranolazine in non-DM and DM rats. First phase: 24 male Wistar rats were separated into 4 groups. The control group (n = 6) received normal saline and the DM groups (n = 18) were treated with a single dose (55mg/kg) of streptozocin (STZ; i.p. injection), then were held for 10, 20, and 30days, respectively. After study duration for each group, the liver CYP 3A2 protein content was determined using western blotting. Second phase: 48 male Wistar rats were classified into two groups of non-DM and DM; and each group was divided into 4 subgroups (n: 6). Experimental groups received oral doses of 20, 40, and 80mg/kg ranolazine. DM and non-DM control groups received normal saline. Treatment lasted for 28days, and then the ECG was recorded. Experimental DM induced by STZ caused a significant decrement in liver CYP3A2 protein content of rats on days 10 and 20 (P < 0.01), and 30 (P < 0.05) compared to the control animals. Significant increases in QT and corrected QT (QTc) intervals (P < 0.01), and bradycardia (P < 0.01) without any significant effect on PR and QRS intervals were observed in DM in comparison with non-DM groups after ranolazine treatment. In summary, DM induction in animals resulted in CYP 3A2 inhibition and the prolongation of QT and QTc interval as well as bradycardia after ranolazine treatment.