title: 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 Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS).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 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.
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, KVSR Siddhartha College of Pharmaceutical Sciences , Vijayawada, Andhra Pradesh , India.
authors.forename: M
authors.initials: M
authors.lastname: Surya Sandeep
authors.forename: V
authors.initials: V
authors.lastname: Sridhar
authors.forename: Y
authors.initials: Y
authors.lastname: Puneeth
authors.forename: P
authors.initials: P
authors.lastname: Ravindra Babu
authors.forename: K
authors.initials: K
authors.lastname: Naveen Babu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015736:Felodipine / Q000493:pharmacokinetics*; D044950:Flavanones / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000959:Antihypertensive Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D044950:Flavanones; D051544:Cytochrome P-450 CYP3A; C005273:naringenin; D019438:Ritonavir; D015736:Felodipine
keywords: CYP3A4; Calcium channel blockers; P-glycoprotein; everted gut sacs; first-pass metabolism; hypertension; naringenin; poor bioavailability