Effects of Quercetin on the Pharmacokinetics of Etoposide after Oral or Intravenous Administration of Etoposide in Rats

Etoposide [4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene)-beta-D-glucopyranoside] is a substrate for P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A. This study was designed to investigate the effects of quercetin (3,5,7,3',4'-pentahydroxyflavanone), a P-gp and CYP3A inhibitor, on the pharmacokinetics of etoposide in rats. Etoposide was administered to rats orally (9 mg/kg) or i.v. (3 mg/kg) without or with quercetin (1, 5 or 15 mg/kg). The plasma concentration of etoposide was determined by high performance liquid chromatography (HPLC) equipped with a fluorescence detector. In the presence of quercetin, the pharmacokinetic parameters of etoposide were significantly altered in the oral group, but not in the i.v. group. The presence of quercetin significantly (5 mg/kg, p<0.05; 15 mg/kg, p<0.0.1) increased the area under the plasma concentration-time curve (AUC) of orally administered etoposide from 43.0 or 53.2%. The presence of 5 or 15 mg/kg of quercetin significantly (p<0.05) decreased the total body clearance (CLIF) of oral etoposide. Consequently, compared to the control group (8.87%), the presence of quercetin significantly (5 mg/kg, p<0.05; 15 mg/kg, p<0.01) increased the absolute bioavailability (AB) of etoposide to 12.7 or 13.6%. The enhanced oral bioavailability of etoposide by quercetin could mainly be due to inhibition of P-gp-mediated efflux and CYP3A-catalyzed metabolism in the intestine by quercetin. The dosage regimen of etoposide in cancer therapy should take drug interaction into consideration when etoposide is administered with quercetin or dietary supplements containing quercetin.