title: Minor effects of the citrus flavonoids naringin, naringenin and quercetin, on the pharmacokinetics of doxorubicin in rats.
abstract: We investigated the effects of naringin, naringenin and quercetin on the pharmacokinetics of doxorubicin in rats. These Citrus flavonoids are known as P-glycoprotein (P-gp) inhibitors and thus suspected to interact with doxorubicin, as shown by in vitro cell studies. Plasma concentrations, tissue distribution, and the urinary and biliary excretion of doxorubicin after intravenous infusion were investigated in rats followed by oral administration of Citrus flavonoids. To evaluate the impact of the biotransformation of Citrus flavonoids on the P-gp inhibition, the inhibitory effects of quercetin and its metabolite on P-gp were compared using ex vivo analysis. Contrary to previous in vitro results, the plasma concentration, biliary and urinary clearance, and tissue distribution of doxorubicin were not altered by pre-treatment with naringin and naringenin. Biliary clearance and urinary clearance were slightly decreased by quercetin, but there was no statistical difference. The minor effects of these flavonoids may relate to their low systemic concentration, due to the biotransformation in vivo situation. S9 stability assay and calcein accumulation assay showed that quercetin was a metabolically unstable compound, and the inhibitory effect of its metabolites on P-gp was negligible. In conclusion, naringin, naringenin and quercetin did not affect the in vivo pharmacokinetics of intravenously administered doxorubicin.
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Korea.
authors.forename: Hyun-seo
authors.initials: HS
authors.lastname: Park
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Oh
authors.forename: Joo hyun
authors.initials: Jh
authors.lastname: Lee
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000652:urine; D000975:Antioxidants / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D002957:Citrus / Q000737:chemistry*; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D044950:Flavanones / Q000494:pharmacology*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D044950:Flavanones; D004317:Doxorubicin; D016572:Cyclosporine; D011794:Quercetin; C005273:naringenin; C005274:naringin