SCREENING THE INFLUENCE OF DILTIAZEM ON ORAL ANTIDIABETIC AGENTS IN EXPERIMENTAL ANIMALS

Abstract

The main aim of this study was to assess the possibility of potential interaction of repaglinide and rosiglitazone with diltiazem. A calcium channel blocker, diltiazem potentially inhibits CYP3A4 and 2C8. Important to note, both drugs meglitinide and thiazolidinediones are actively metabolised by these isoenzymes. In the present study, various animal models like healthy rats, healthy rabbits and diabetic rats were used to assess possible interactions between the above said drugs. In normoglycemic rats, repaglinide induced hypoglycemia with onset at 1st h and duration was from 1st to 8th h, whereas in case of rosiglitazone, onset was at 2nd h and duration was up to 18 h. Normoglycemic animals pretreated with diltiazem had no effect on onset but duration of hypoglycemia induced by repaglinide was enhanced, whereas diltiazem caused early onset of hypoglycemia induced by rosiglitazone. In normoglycemic rabbits, hypoglycemia caused by repaglinide started at 1st h and continued upto 8th h, whereas rosiglitazone effect started at 4th h and continued upto 12th h. Diltiazem pre-treatment increased the duration of hypoglycemia caused by repaglinide. Diltiazem caused early onset and increase duration of hypoglycemia induced by rosiglitazone. After obtaining satisfactory results from the above two animal models, study was conducted on streptozotocin-induced diabetic rats. In diabetic rats, diltiazem has no hypoglycemic effect on group II animals. Repaglinide and rosiglitazone induced hypoglycemia from 1st h to 8th h and 2nd h to 18th h, respectively. Diltiazem pre-treatment had no effect on onset but significantly enhanced the peak and duration of hypoglycemia induced by repaglinide. Diltiazem pretreatment not only induced early onset but also enhanced peak and duration of hypoglycemia induced by rosiglitazone. Based on the results, it is concluded that the isoenzymes which are involved in the metabolism of repaglinide and rosiglitazone are sensitive to diltiazem and hence there is a need to go for therapeutic drug monitoring to readjust the dose and frequency of co-administration of these drugs.