Effect of herbal bioenhancer (naringenin) on the pharmacokinetics of diltiazem in rats via CYP3A4 and P-glycoprotein inhibition

CYP3A4 and P-gp substrate is diltiazem and naringenin has been observed to affect both CYP3A4 and P-gp. The goal of this study was to observe how naringenin affected the pharmacokinetics (PK) of diltiazem in rats as well as absorption using everted gut sacs of rat in vitro. After 20 min, rats were administered orally with naringenin (12.5, 25 and 50 mg/kg) and then 15 mg/kg of diltiazem was also administered for 15 repeated days orally. In a single dosage PK study (SDS), blood was taken from the tail vein on the 1st day and in a multiple dosing PK study (MDS) on the 15th day. Thermokinetic was used to calculate the PK parameters. In a dose-dependent manner, naringenin pretreatment enhanced the Cmax and the AUC of diltiazem. At a dosage of naringenin 100 mg/kg, the Cmax of diltiazem increased from 39.276 +/- 2.485 to 72.394 +/- 5.152 and 44.982 +/- 5.348 to 85.372 +/- 5.263 ng/ml in SDS and MDS, respectively. In SDS and MDS, the AUC of diltiazem increased considerably from 818.206 +/- 69.247 to 1448.781 +/- 91.588 and 1730.362 +/- 145.314 to 2677.052 +/- 122.625 (ng/ml/h). In vitro test results revealed that diltiazem absorption was increased with naringenin and verapamil (a known standard P-gp and CYP3A4 inhibitor). The findings suggested that naringenin enhanced diltiazem absorption in the intestine due to P-gp and CYP3A4 inhibition.