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Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats.

ABSTRACT: The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 ?M, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min??g/mL vs. 25.7 ± 9.98 min??g/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food-drug interactions should be considered.

SUBMITTER: Song YK

PROVIDER: S-EPMC7285070 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats.

Song Yoo-Kyung YK Yoon Jin-Ha JH Woo Jong Kyu JK Kang Ju-Hee JH Lee Kyeong-Ryoon KR Oh Seung Hyun SH Chung Suk-Jae SJ Maeng Han-Joo HJ

Pharmaceutics 20200426 5

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of querce ...[more]

PMID: 32357395

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Project description:The aim of the present study was to evaluate whether quercetin (Que) modulates the mRNA and protein expression levels of drug‑metabolizing enzymes (DMEs) and drug transporters (DTs) in the small intestine and liver, and thus modifies the pharmacokinetic profile of cyclosporine (CsA) in rats. This two‑part study evaluated the pharmacokinetic profiles of CsA in the presence or absence of Que (experiment I) and the involvement of DMEs and DTs (experiment II). In experiment I, 24 rats received single‑dose CsA (10 mg/kg) on day 1, single‑dose Que (25, 50 and 100 mg/kg/day; eight rats in each group) on days 3‑8, and concomitant CsA/Que on day 9. In experiment II, the mRNA and protein expression levels of cytochrome P (CYP)3A1, CYP3A2, UDP glucuronosyltransferase family 1 member A complex locus, organic anion‑transporting polypeptide (OATP)2B1, OATP1B2, P‑glycoprotein, breast cancer resistance protein, and multidrug resistance‑associated protein 2 in the small intestine and liver of rats were analyzed following oral administration of Que at 25, 50 and 100 mg/kg in the presence or absence of CsA (10 mg/kg) for seven consecutive days. Co‑administration of Que (25,50 and 100 mg/kg) decreased the maximum serum concentration of CsA by 46, 50 and 47% in a dose‑independent manner. In addition, the area under the curve to the last measurable concentration and area under the curve to infinite time were decreased, by 21 and 16%, 30 and 33%, and 33 and 34% (P<0.01), respectively. However, the mRNA and protein expression levels of the above‑mentioned DMEs and DTs were inhibited by Que in a dose‑dependent manner (P<0.01) to a similar extent in the small intestine and liver. It was demonstrated that Que was able to reduce the bioavailability of CsA following multiple concomitant doses in rats. Overlapping modulation of intestinal and hepatic DMEs and DTs, as well as the DME‑DT interplay are potential explanations for these observations.

Dataset Information

Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats.

Publications

Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats.

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