Jun-Shik Choi

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 (IC50) 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 (AUC0−∞, 31.2-136.0% greater) of oral doxorubicin. Quercetin also significantly increased the peak plasma concentration (Cmax) of doxorubicin, while there was no significant change in Tmax and T1/2 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.

Enhanced bioavailability by buccal administration of triamcinolone acetonide from the bioadhesive gels in rabbits.

The pharmacokinetics and bioavailability of triamcinolone acetonide were determined to investigate buccal absorption from the mucoadhesive gels in rabbits. The enhancing effect of sodium deoxycholate as an enhancer on the buccal absorption of triamcinolone acetonide from the mucoadhesive gels was evaluated in rabbits. Thus, 2 mg/kg of triamcinolone acetonide was administered from the mucoadhesive gels containing an enhancer (enhancer group) or not (control group) via the buccal routes and compared with intravenous routes (1 mg/kg, i.v. group). AUC of the control, enhancer and i.v group were 2374+/-915, 3778+/-1721 and 3945+/-2085 h ng/ml, respectively, and the absolutive bioavailability of enhancer or i.v to control group were 159.14 or 332.35%, respectively. The average C(max) of control and enhancer group were 263+/-159 and 362+/-201 ng/ml, and the mean T(max) of the control group and enhancer group were 5.00+/-1.67 and 4.33+/-0.82 h, respectively, but there was no significant difference. As the triamcinolone acetonide gels containing sodium deoxycholate as an enhancer was administered to rabbits via the buccal routes, the relative bioavailability showed about 1.59-fold compared with the control group. Buccal administration of triamcinolone acetonide gels containing sodium deoxycholate as an enhancer to rabbits showed a relatively constant, sustained blood concentration with minimal fluctuation.

Enhanced dissolution of furosemide by coprecipitating or cogrinding with crospovidone

Abstract To increase the dissolution rate of furosemide, cogrinding or coprecipitating of furosemide with crospovidone was carried out. The 1:2 (w/w) ground mixture of furosemide with crospovidone was prepared by cogrinding in a ceramic ball mill and the coprecipitate was prepared by the solvent method using methanol. The dissolution test was carried at 37±0.5°C and 150 rpm in simulated gastric fluids (pH 1.2). The dissolution rate of furosemide was rapid and markedly enhanced by cogrinding or coprecipitating with crospovidone. The X-ray diffraction, IR, DTA and TGA studies showed the physicochemical modifications of the furosemide from the ground mixture or the coprecipitate. Furosemide alone or furosemide contained within a physical mixture was crystalline in nature, whereas furosemide in the ground mixture or the coprecipitate was not crystalline even when preserved at room temperature for 1 year. An interaction, in the ground mixture or in the coprecipitate, such as an association between the functional groups of furosemide and crospovidone may have occurred at the molecular level, changed the thermal property and increased the dissolution of furosemide. The cogrinding or coprecipitating techniques with crospovidone provide a promising way to increase the dissolution rate of poorly soluble drugs.

Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats.

The effects of epigallocatechin gallate (EGCG) on the oral bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. A single dose of tamoxifen was administered intravenously (2 mg/kg) and orally (10 mg/kg) with or without epigallocatechin (0.5, 3 and 10 mg/kg) to rats. The presence of EGCG significantly altered the pharmacokinetics of orally administered tamoxifen. Compared with the oral control group (given tamoxifen alone), the area under the plasma concentration–time curve and the peak plasma concentration of tamoxifen significantly (P<0.05 for 3 mg/kg of EGCG, P<0.01 for 10 mg/kg of EGCG) increased 48.4–77.0 and 57.1–89.7%, respectively. Consequently, the absolute bioavailability of tamoxifen in the presence of EGCG (3 and 10 mg/kg) was 48.9–78.1%, which was significantly enhanced (P<0.05 for 3 mg/kg of EGCG, P<0.01 for 10 mg/kg of EGCG) compared with the oral control group (23.7%). Moreover, the relative bioavailability of tamoxifen was 1.48–1.77-fold greater than that of the control group. EGCG at a dose of 10 mg/kg significantly increased the area under the plasma concentration–time curve (P<0.05, 40.3%) of 4-hydroxytamoxifen, but the metabolite–parent ratio of 4-hydroxytamoxifen was also significantly altered (P<0.05 for 10 mg/kg of EGCG), implying that the formation of 4-hydroxytamoxifen was considerably affected by EGCG. The increase in bioavailability of tamoxifen is likely to be due to the decrease in first-pass metabolism in the intestine and liver by inhibition of P-glycoprotein and CYP3A by EGCG. The increase in oral bioavailability of tamoxifen in the presence of EGCG should be taken into consideration of potential drug interactions between tamoxifen and EGCG.

Role of monocarboxylic acid transporters in the cellular uptake of NSAIDs

The present study investigated the cellular uptake mechanism of non‐steroidal anti‐inflammatory drugs (NSAIDs) in Caco‐2 cells. Diflunisal, diclofenac, ketoprofen and naproxen exhibited a strong inhibition effect on the cellular uptake of [14C]‐benzoic acid in Caco‐2 cells with IC50 values of 0.05–0.44 mm. The inhibition of naproxen and ketoprofen against the membrane transport of [14C]‐benzoic acid appeared to be competitive, with Ki values of 0.22 and 0.38 mm, respectively. The membrane permeability of naproxen and ketoprofen was concentration dependent, implying that the cellular uptake pathway of ketoprofen and naproxen was saturable at the higher concentration. Furthermore, the cellular accumulation of ketoprofen was significantly reduced in the presence of benzoic acid and l‐lactic acid, two known substrates of monocarboxylic acid transporter 1 (MCT1). These results suggest that MCT1 contributes at least in part to the carrier‐mediated transport of NSAIDs containing a carboxylic acid moiety across the apical membrane in Caco‐2 cells.

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg−1) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg−1). While co‐administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the Cmax and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg−1 quercetin. There was no significant change in Tmax and terminal plasma half‐life (t½) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P<0.05) than those from the control group. Metabolite‐parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4‐mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin‐containing dietary supplement with verapamil requires close monitoring for potential drug interaction.

Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats

Verapamil is known to be a P-glycoprotein (P-gp) substrate and norverapamil is formed via hepatic cytochrome P450 (CYP 3A) in the rat. Epigallocatechin gallate (EGCG), a flavonoid, was reported to be an inhibitor of both P-gp and CYP3A. Hence, it could be expected that EGCG could alter the pharmacokinetics of verapamil. In this study, 9 mg/kg verapamil was administered orally to Sprague-Dawley rats 30 min after the oral administration of 2 and 10 mg/kg of oral EGCG. Compared with the controls, the AUC values of both verapamil (74.3% and 111% increase for 2 and 10 mg/kg EGCG, respectively) and norverapamil (51.5% and 87.2% increase for 2 and 10 mg/kg EGCG, respectively) were significantly greater in the presence of EGCG. However, compared with the controls, both the AUC and the relative bioavailability of verapamil were significantly (p<0.01) increased by 74.3-111% in the presence of EGCG. The likely explanation is inhibition of P-gp. Inhibition of CYP3A would increase the AUC of verapamil but decrease the AUC of norverampil. However, inhibition of P-gp would lead to an increase of AUC of both verapamil and norverapamil.

Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin.

This study aimed to investigate the effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats. Intravenous (6 mg/kg) or oral (2 mg/kg) etoposide was administered to rats in the absence and the presence of oral curcumin (0.4, 2 or 8 mg/kg). The effects of curcumin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Curcumin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration (IC(50) ) of 2.7 µM. In addition, curcumin (10 µm) significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given etoposide alone), curcumin (2 or 8 mg/kg) increased significantly the oral bioavailability (AUC and C(max) ) of etoposide. Consequently, the extent of absolute oral bioavailability (F) of etoposide with curcumin was significantly enhanced compared with that in the control group. In contrast, curcumin did not affect the pharmacokinetics of etoposide after intravenous administration. Therefore, the enhanced oral bioavailability of etoposide in the presence of curcumin might be due mainly to inhibition of the P-gp efflux pump in the small intestine and possibly by reduced first-pass metabolism of etoposide in the small intestine by inhibition of CYP3A activity in rats. The combined use of curcumin may be helpful to improve the F of etoposide in chemotherapeutic applications.

Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats: Possible role of cytochrome p450 3A4 and P-glycoprotein inhibition by baicalein

The purpose of this study was to investigate the effects of baicalein on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats. Tamoxifen and baicalein interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in baicalein being taken concomitantly with tamoxifen as a combination therapy to treat orprevent cancer diseases. Pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined in rats after an oral administration of tamoxifen (10 mg/kg) to rats in the presence and absence of baicalein (0.5, 3, and 10 mg/kg). Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve and the peak plasma concentration of tamoxifen were significantly increased by 47.6–89.1% and 54.8–100.0%, respectively. The total body clearance was significantly decreased (3 and 10 mg/kg) by baicalein. Consequently, the absolute bioavailability of tamoxifen in the presence of baicalein (3 and 10 mg/kg) was significantly increased by 47.5–89.1% compared with the oral control group (20.2%). The metabolite-parent AUC ratio of tamoxifen was significantly reduced, implying that the formation of 4-hydroxytamoxifen was considerably affected by baicalein. Baicalein enhanced the oral bioavailability of tamoxifen, which may be mainly attributable to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver, and inhibition of the P-gp efflux pump in the small intestine and/or reduction of total body clearance by baicalein.

Effects of silibinin, inhibitor of CYP3A4 and P-glycoprotein in vitro, on the pharmacokinetics of paclitaxel after oral and intravenous administration in rats.

Silibinin, a flavonoid, is an inhibitor of P-glycoprotein (P-gp)-mediated efflux transporters, and its oxidative metabolism is catalyzed by CYP3A4. The purpose of this study was to investigate the effect of oral silibinin on the bioavailability and pharmacokinetics of orally and intravenously administered paclitaxel in rats. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (4 mg/kg) administration in the presence and absence of silibinin (0.5, 2.5 or 10 mg/kg). The effect of silibinin on the P-gp as well as CYP3A4 activity was also evaluated. Silibinin inhibited CYP3A4 enzyme activity with an IC50 of 1.8 µmol/l. In addition, silibinin significantly inhibited P-gp activity. Compared to the control group, silibinin significantly (p < 0.05 by 2.5 mg/kg, p < 0.01 by 10 mg/kg) increased the area under the plasma concentration-time curve (65.8–101.7% higher) of oral paclitaxel. Silibinin also significantly increased (p < 0.05 by 2.5 mg/kg, 31.0% higher; p < 0.01 by 10 mg/kg, 52.9% higher) the peak plasma concentration of paclitaxel. Consequently, the absolute bioavailability of paclitaxel was increased by silibinin compared to that in the control group, and the relative bioavailability of oral paclitaxel was increased 1.15- to 2.02-fold. The intravenous pharmacokinetics of paclitaxel were not affected by the concurrent use of silibinin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability in the presence of silibinin could mainly be due to the increased intestinal absorption of paclitaxel via P-gp inhibition.