Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin.

Quercetin, a flavonoid, is an inhibitor of P-glycoprotein-mediated efflux transport, and its oxidative metabolism is catalyzed by CYP enzymes. Thus, it is expected that the pharmacokinetics of both intravenous and oral doxorubicin can be changed by quercetin. The purpose of this study was to investigate the effect of oral quercetin on the bioavailability and pharmacokinetics of orally and intravenously administered doxorubicin in rats. The effects of quercetin on the P-glycoprotein (P-gp) and CYP3A4 activities were also evaluated. Quercetin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 1.97 µM. In addition, quercetin significantly enhanced the intracellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of doxorubicin were determined in rats after oral (50 mg/kg) or intravenous (10 mg/kg) administration of doxorubicin to rats in the presence and absence of quercetin (0.6, 3 or 15 mg/kg). Compared to control, quercetin significantly (p < 0.05 for 0.6 mg/kg, p < 0.01 for 3 and 15 mg/kg) increased the area under the plasma concentration-time curve (AUC(0-∞), 31.2-136.0% greater) of oral doxorubicin. Quercetin also significantly increased the peak plasma concentration (C(max)) of doxorubicin, while there was no significant change in T(max) and T(1/2) of doxorubicin. Consequently, the absolute bioavailability of doxorubicin was increased by quercetin compared to control, and the relative bioavailability of oral doxorubicin was increased by 1.32 to 2.36 fold. In contrast, the pharmacokinetics of intravenous doxorubicin were not affected by quercetin. These results suggest that the quercetin-induced increase in bioavailability of oral doxorubicin can be attributed to enhanced doxorubicin absorption in the gastrointestinal tract via quercetin-induced inhibition of P-gp and reduced first-pass metabolism of doxorubicin due to quercetin-induced inhibition of CYP3A in the small intestine and/or in the liver rather than reduced renal and/or hepatic elimination of doxorubicin. Therefore, it appears that the development of oral doxorubicin preparations is possible, which will be more convenient than the intravenous dosage forms. Therefore, concurrent use of quercetin provides a therapeutic benefit - it increases the bioavailability of doxorubicin administered orally.

Effects of verapamil on etoposide pharmacokinetics after intravenous and oral administration in rats.

Etoposide is mainly metabolized by cytochrome P450 (CYP) 3A and is a substrate for P-glycoprotein (P-gp). This study examined the effects of verapamil, a CYP3A and P-gp inhibitor, on the pharmacokinetics of etoposide in rats. A single dose of etoposide was administered via oral (p.o.; 10 mg/kg) or intravenous (i.v.; 3.3 mg/kg) routes to rats alone (control animals) or together in combination with verapamil (2 or 6 mg/kg; experimental animals). The presence of verapamil significantly increased the area under the plasma concentration-time curve (AUC); (P < 0.05; 39.2-47.6%) and significantly reduced (P < 0.01; 27.8-31.2%) the total body clearance (CLt) of p.o. administered etoposide. The absolute bioavailability (F) of etoposide increased by 1.38- to 1.47-fold. The presence of verapamil significantly increased (P < 0.01; 38.3-38.9%) the AUC and significantly reduced (P < 0.01; approximately 27%) the total body clearance (CLt) of i.v. administered etoposide. This increased bioavailability suggests that verapamil inhibits metabolic activity and elimination etoposide. The increased bioavailability of etoposide in the presence of verapamil should be taken into consideration for dosage regimens due to a potential drug interaction (DI).

Effects of morin on the bioavailability of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats.

This study examined the effect of morin on the bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, in rats. A single dose of tamoxifen was administered to rats intravenously (2 mg/kg) or orally (10 mg/kg), with or without morin (3 or 10 mg/kg). The presence of morin significantly altered the pharmacokinetics of the orally administered tamoxifen. Compared with the oral control group (given tamoxifen alone), the total body clearance (CL/F) of tamoxifen in the presence of morin was significantly reduced (by 35.9-40.8%, p<0.01). The area under the plasma concentration-time curve (AUC(0-infinity)) and the peak plasma concentration (Cmax) of tamoxifen significantly (p<0.05 for 3 mg/kg of morin, p<0.01 for 10 mg/kg of morin) increased by 50.6-68.9% and 65.1-80.9%, respectively. Consequently, the absolute bioavailability (AB) of tamoxifen in the presence of morin was 37.4-40.5%, which was enhanced significantly (p<0.05) compared with the oral control group (23.9%). The relative bioavailability (RB) of tamoxifen was 1.56 to 1.68 times higher than the control group. The increased bioavailability of tamoxifen is likely to be due to the decrease in the first-pass metabilism by the intestines and liver. Morin at a dose of 10 mg/kg significant increased the AUC(0-infinity), of 4-hydroxytamoxifen (by 50.9%, p<0.05) but the metabolite:parent ratio (MR) of 4-hydroxytamoxifen was not altered significantly, suggesting that the formation of 4-hydroxytamoxifen is not affected considerably by morin. The increased bioavailability of tamoxifen in the presence of morin should be taken into consideration for dosage regimens due to potential drug interaction.

Enhanced bioavailability of verapamil after oral administration with hesperidin in rats.

The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1-96.8% and the peak concentration (C(max)) of verapamil by 98.3-105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6-49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (T(max)), the elimination rate constant (K(el)) and the terminal half-life (T(1/2)) of verapamil in the presence of hesperidin. The AUC and C(max) of norverapamil were significantly (p<0.05) higher in rats co-administrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary.

Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats.

This study investigated the effects of orally administered morin, an inhibitor of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), on the pharmacokinetics of orally and intravenously administered nicardipine in rats. Nicardipine is reportedly a substrate for CYP3A4 and P-gp. Nicardipine was administered orally (12 mgkg(-1)) with or without orally administered morin (1.5, 7.5 and 15 mgkg(-1)), and intravenously (4 mgkg(-1)) with or without orally administered morin (7.5 and 15 mgkg(-1)). In the presence of morin, the pharmacokinetic parameters of nicardipine were significantly altered in the oral group but not in the intravenous group, suggesting that CYP3A-mediated metabolism of nicardipine in the liver is not significantly inhibited by morin. The presence of 7.5 and 15 mgkg(-1) of morin significantly increased (P < 0.01, 67.8-112%) the area under the plasma concentration-time curve and the peak plasma concentration (P < 0.01, 53.5-93.1%) of orally administered nicardipine. The presence of 7.5 and 15 mgkg(-1) of morin significantly decreased (P < 0.01, 40.4-52.8%) the total body clearance of orally administered nicardipine compared with the control group. The enhanced oral bioavailability of nicardipine suggests that intestinal-mediated CYP3A4 metabolism and P-gp-mediated efflux of nicardipine are inhibited by morin. Based on these results, concomitant use of morin or morin-containing dietary supplements with nicardipine may require close monitoring for potential drug interactions.

Pharmacokinetic interaction between fluvastatin and diltiazem in rats.

The present study aimed to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem in rats. Pharmacokinetic parameters of diltiazem were determined in rats following an oral administration of diltiazem (15 mg/kg) in the presence and absence of fluvastatin (0.6 and 2.0 mg/kg). Compared with the control given diltiazem alone, the C(max) and AUC of diltiazem increased by 30-70% in rats with the concurrent use of fluvastatin, while there was no significant change in T(max) and the plasma half-life (T(1/2)) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of fluvastatin were significantly higher (p<0.05) than those from the control group, implying that fluvastatin could reduce the presystemic extraction of diltiazem. In conclusion, the concurrent use of fluvastatin significantly enhanced the oral exposure of diltiazem in rats.