Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

Abstract

ABSTRACT:The aim of this study was to report the effect of diabetes mellitus on the pharmacokinetics of verapamil in a route-dependent manner. Diabetes in rats was induced by streptozotocin. Plasma concentrations of verapamil and its metabolite, norverapamil, were measured after oral (10 mg/kg) or intravenous (1 mg/kg) administration. The concentrations of verapamil in portal plasma after oral administration were also determined. Norverapamil formation was used for assessing CYP3A activity in hepatic and intestinal microsomes of diabetic rats. The protein levels of CYP3A1 and CYP3A2 in liver and intestine were measured by Western blot. It was found that diabetes significantly increased the plasma concentration of verapamil and norverapamil after oral administration, which resulted in a 74% increase in the area under the concentration-time curve (AUC) of verapamil, but the ratio of AUC (norverapamil) /AUC (verapamil) was significantly decreased by 38%. In contrast, diabetes significantly decreased the AUC of verapamil by 22% after intravenous administration. Diabetes also resulted in increased AUC of verapamil in portal vein by 3.8-fold compared with that in control rats. The absolute bioavailability of verapamil was higher than that of control rats. An in vitro study showed that increased CYP3A activity in the hepatic microsome and decreased CYP3A activity in the intestinal microsome were accompanied by an increase and decrease in the protein expression of CYP3A1/2 in liver and intestine of diabetic rats, respectively. In conclusion, diabetes mellitus revealed a tissue-specific effect on CYP3A activity and expression (induced in liver and inhibited in intestine), resulting in opposite pharmacokinetic behaviors of verapamil after oral and intravenous administration to diabetic rats.

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

“…Similarly, a significant increase in the levels of Cyp3a1 mRNA was observed in the liver of DM rats. We previously reported significant enhancement of Cyp3a in hepatic microsomes of DM rats using norverapamil formation from verapamil, another type of Cyp3a probe [18,19] . All of these results suggested that the enhanced activity and expression of hepatic Cyp3a were the main contributors to the increases in systemic clearance of simvastatin and simvastatin acid.…”

“…Preparation of hepatic microsomes and metabolism of simvastatin in hepatic microsomes Hepatic microsomes of experimental rats were prepared according to the methods previously described [18,19] . The microsomal pellets were re-suspended in phosphate-buffered saline (PBS) (pH 7.4) containing 20% glycerol and stored at -80 °C.…”

“…Both HFD rats and DM rats were fed using a high-fat diet. After 4 weeks of dietary manipulation, the DM rats received an intraperitoneal injection of STZ (35 mg/kg, dissolved in pH 4.5 citrate buffer) [19] . Both HFD and CON rats received only an equivalent volume of citrate buffer.…”

“…The diabetic rats were developed according to our method previously described [19] . The rats were randomly divided into three groups: age-matched control (CON) group, high fat diet (HFD) group and diabetes (DM) group.…”

“…Recent studies have shown that OATP1B1 plays a clinically important role in the hepatic elimination of several drugs including statins, via mediating the hepatic uptake [11][12][13][14][15] . Both clinical trials and animal experiments have demonstrated that DM may alter the pharmacokinetic behaviors of some drugs via regulating the expressions and activities of cytochrome P450s (CYP450s) and drug transporters in the liver [16][17][18][19][20][21][22] . Breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) have also been reported to mediate statin transport [11,23,24] .…”