Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro

Abstract

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10 mg/kg, p.o. and naringenin (25, 50 and 100 mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the Cmax and increased the AUCtotal of felodipine in dose-dependent manner. The Cmax of felodipine was increased from 173.25 ± 14.65 to 275.61 ± 44.62 and 223.26 ± 26.35 to 561.32 ± 62.53 ng/mL in SDS and MDS, respectively, at the dose of naringenin 100 mg/kg. The AUCtotal of felodipine was significantly (p < 0.001) increased from 2050.48 ± 60.57 to 3650.22 ± 78.61 and 3276.51 ± 325.61 to 7265.25 ± 536.11 (ng/mL/h) in SDS and MDS, respectively. The permeability of felodipine was increased in presence of naringenin and ritonavir (standard P-glycoprotein (P-gp) and Cytochrome P450 (CYP)3A4 inhibitor). Felodipine is a substrate of CYP3A4, and naringenin was reported to be a modulator of P-gp and CYP3A4. These results suggest that naringenin significantly increased the Cmax and AUC of felodipine is due to P-gp and CYP3A4 inhibition.

Safety evaluation of naringenin upon experimental exposure on rat gastrointestinal epithelium for novel optimal drug delivery

“…This was also supported by other authors using naringenin as P-gp inhibitor in their research work, although with a different P-gp substrate (Surya Sandeep et al, 2013).…”

Flavonoids as modulators of metabolic enzymes and drug transporters

“…In both single-dose and multiple-dose administration (15 days), oral naringenin increased the bioavailability of orally administered felodipine, a selective calcium channel blocker used in the treatment of hypertension. 32 With regard to structure-activity relationships, most in vitro studies support the importance of hydrophobicity for CYP3A4 inhibition (Fig. 2).…”

“…CYP3A4 inhibitory activity of naringenin was confirmed in vivo . In both single‐dose and multiple‐dose administration (15 days), oral naringenin increased the bioavailability of orally administered felodipine, a selective calcium channel blocker used in the treatment of hypertension …”

Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C

“…Among various drug metabolizing enzymes, cytochrome P450 monooxygenase (CYP) is typically involved in clinically significant interactions between prescribed drugs and herbs [5][6][7] . Grapefruit (Citrus paradisi), St. John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba) and licolice (Glycyrrhiza glabra) have all been reported to alter the CYP-mediated metabolism and efficacy of anticoagulants, anticancer drugs, antiretroviral drugs, antihyperlipidemic drugs, immunosuppressants and/or antidepressants [8][9][10][11][12][13][14] . Therefore, examining CYP-mediated herb-drug interactions and their mechanisms in animals and human could be a good basis for the optimal design of drug and herb-based therapies.…”