Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in 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 Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS).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 C_max and increased the AUC_total of felodipine in dose-dependent manner. The C_max 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 AUC_total 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 C_max and AUC of felodipine is due to P-gp and CYP3A4 inhibition.

• Calcium channel blockers
• CYP3A4
• everted gut sacs
• first-pass metabolism
• hypertension
• naringenin
• poor bioavailability
• P-glycoprotein

Acknowledgements

The authors are grateful to N. Venkateswarlu, President, and P. Lakshmana Rao, Secretary of SAGTE, for providing necessary facilities. The authors thank Dr. G. Devalarao, Principal, and Dr. Buchi. N. Nalluri, Director for PG studies and Research of KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, for their encouragement. The authors are grateful for the generous gifts of felodipine, nitrendipine and ritonavir from Orchid Health Care, Chennai, India, and Sipra Labs Ltd., Hyderabad, India, respectively.