scholarly journals Negligible Effect of Quercetin in the Pharmacokinetics of Sulfasalazine in Rats and Beagles: Metabolic Inactivation of the Interaction Potential of Quercetin with BCRP

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 1989
Author(s):  
Ju-Hee Oh ◽  
Dokeun Kim ◽  
Haejun Lee ◽  
Gyeonghee Kim ◽  
Taehoon Park ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
Induction Effect ◽  
Cancer Resistance ◽  
Mdckii Cells ◽  
Liver And Kidney ◽  
Resistance Protein ◽  
Pharmacokinetic Drug

Breast cancer resistance protein (BCRP) mediates pharmacokinetic drug interactions. This study evaluated the potential of quercetin to inhibit and induce BCRP in vitro and in vivo. The inhibition of BCRP was investigated for quercetin and its metabolites using BCRP/mBcrp1-overexpressing MDCKII cells by flow cytometry. The induction of BCRP was investigated in LS174T cells using quantitative PCR. The expression of rat BCRP in rat small intestine, liver, and kidney was also measured after multiple administrations of quercetin in rats (50, 100, and 250 mg/kg, seven days). The in vivo pharmacokinetic changes of sulfasalazine following single or multiple administration of quercetin in rats and beagles were investigated. Although the induction effect of quercetin on BCRP was observed in vitro, the in vivo expression of rat BCRP was not changed by multiple quercetin administrations. Oral administration of quercetin did not affect the plasma concentration or pharmacokinetic parameters of sulfasalazine, regardless of dose and dosing period in either rats or beagles. In addition, the inhibitory effect of quercetin metabolites on BCRP/mBcrp1 was not observed. These results suggest that the in vivo drug interaction caused by quercetin via BCRP was negligible, and it may be related to the metabolic inactivation of quercetin for the inhibition of BCRP.

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

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 397
Author(s):  
Yoo-Kyung Song ◽  
Jin-Ha Yoon ◽  
Jong Kyu Woo ◽  
Ju-Hee Kang ◽  
Kyeong-Ryoon Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
Concentration Dependent Manner ◽  
Resistance Protein

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 μM, 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∙μg/mL vs. 25.7 ± 9.98 min∙μg/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.

Oleic acid increases uptake and decreases the P-gp-mediated efflux of the veterinary anthelmintic Ivermectin

Drug Research ◽  
2018 ◽  
Vol 69 (03) ◽  
pp. 173-180 ◽  
Author(s):  
Bilal Houshaymi ◽  
Nadine Nasreddine ◽  
Mamdouh Kedees ◽  
Zeina Soayfane
Keyword(s):  
Oleic Acid ◽  
Intestinal Mucosa ◽  
Drug Formulation ◽  
Dependent Manner ◽  
Cancer Resistance ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
Complex Micelles

AbstractThe bioavailability of ivermectin is modulated by lipid-based formulations and membrane efflux transporters such as Breast Cancer Resistance Protein and P-glycoprotein (BCRP and P-gp). We have investigated the effect of oleic acid on the uptake of ivermectin in vitro using Caco-2 cells and in vivo in the intestines of wild-type mice. Complex micelles (M) with oleic acid induced a significant increase (e. g. for M3 was 7-fold, p≤0.001) in the uptake of the drug in a time-dependent manner with no involvement of cholesterol in the mechanism. In vivo results showed a significant increase in the concentration of plasma and intestinal mucosa ivermectin (p≤0.01) in mice receiving oleic acid-based drug formulation. We also examined the expression of the drug efflux transporter, BCRP and P-gp in Caco-2 cells and found a significant decrease (p≤0.001) in their level in the presence of 5 mM oleic acid. Treatment of mice with oleic acid-based formulation showed a significant decrease in the activity of P-gp in the intestinal mucosa (p≤0.01). This study highlighted the effect of oleic acid in decreasing the expression and the activity of P-gp-mediated ivermectin efflux and in limiting the drug absorption by increasing its uptake and bioavailability in Caco-2 cells and intestine, respectively.

scholarly journals Modulation of Placental Breast Cancer Resistance Protein by HDAC1 in Mice: Implications for Optimization of Pharmacotherapy During Pregnancy

2021 ◽  
Author(s):  
Chuan Wang ◽  
Dan Ma ◽  
Yimin Hua ◽  
Hongyu Duan
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Negative Control ◽  
Great Promise ◽  
Cancer Resistance ◽  
Gene Expressions ◽  
Time Curve ◽  
Resistance Protein

AbstractBreast cancer resistance protein (BCRP/ABCG2) is a critical drug efflux transporters by limiting drugs’ transplacental transfer rates. More investigations on the regulation of placental BCRP offer great promise for enabling pronounced progress in individualized and safe pharmacotherapy during pregnancy. Histone deacetylases (HDACs) play an important role in epigenetic regulation of placental genes. It was reported recently by us that HDAC1 was involved in placental BCRP regulation in vitro. The aim of this study was to further explore the effect of HDAC1 on placental BCRP expression and functionality in animals. Randomly assigned C57BL pregnant dams received intraperitoneal injections of a negative control siRNA or Hdac1 siRNA from embryonic day 7.5 (E7.5) to E15.5, respectively. At E16.5, glyburide (GLB), a probe for evaluating placental BCRP efflux functionality, was injected via the tail vein. Animals were sacrificed through cervical dislocation at various times (5–180 min) after drug administration. The maternal blood, placentas, and fetal-units were collected. GLB concentrations were determined by a validated high-performance liquid chromatography/mass spectrometry (HPLC-MS) assay. Real-time quantitative PCR (qRT-PCR), Western blot, and immunohistochemical (IHC) analysis were employed to identify mRNA/protein levels and localization of gene expressions, respectively. It was noted that Hdac1 inhibition significantly decreased placental Bcrp expression, with markedly increases of GLB concentrations and area under the concentration-time curve (AUC) in fetal-units. Particularly, the ratios of fetal-unit/maternal plasma GLB concentrations were also significantly elevated following Hdac1 repression. Taken together, these findings suggested that HDAC1 was involved in positive regulation of placental BCRP expression and functionality in vivo.

scholarly journals Relevance of Breast Cancer Resistance Protein to Pharmacokinetics of Florfenicol in Chickens: A Perspective from In Vivo and In Vitro Studies

2018 ◽  
Vol 19 (10) ◽  
pp. 3165 ◽  
Author(s):  
Yang Liu ◽  
Li Guo ◽  
Mire Zloh ◽  
Yujuan Zhang ◽  
Jinhu Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Mdck Cells ◽  
Binding Pocket ◽  
Chicken Breast ◽  
Pharmacokinetic Studies ◽  
Cancer Resistance ◽  
Resistance Protein

Florfenicol (FFC) is a valuable synthetic fluorinated derivative of thiamphenicol widely used to treat infectious diseases in food animals. The aims of the study were to investigate whether FFC is a substrate for the breast cancer resistance protein (BCRP) and whether the transporter influences oral availability of FFC. In vitro transport assays using MDCK-chAbcg2 cells were conducted to assess chicken BCRP-mediated transport of FFC, while in vivo pharmacokinetic experiments with single or combined BCRP inhibitor gefitinib were employed to study the role of BCRP in oral FFC disposition. According to U.S. Food and Drug Administration (FDA) criteria, FFC was found to be a potential BCRP substrate due to the net efflux ratio being over 2.0 (2.37) in MDCK cells stably transfected with chicken BCRP and the efflux completely reversed by a BCRP inhibitor (Gefitinib). The molecular docking results indicated that florfenicol can form favorable interactions with the binding pocket of homology modeled chicken BCRP. Pharmacokinetic studies of FFC in different aged broilers with different expression levels of BCRP showed that higher BCRP expression would cause a lower Area Under Curve (AUC) and a higher clearance of FFC. In addition, more extensive absorption of florfenicol after the co-administration with gefitinib (a BCRP inhibitor) was observed. The overall results demonstrated that florfenicol is a substrate of the chicken breast cancer resistant protein which in turn affects its pharmacokinetic behavior.

scholarly journals In vivo and in vitro antidiabetic properties of alkaloids extract from Salvia chudaei

2021 ◽  
pp. 45-53
Author(s):  
Mohammed Tlili ◽  
Roukia Hammoudi ◽  
Mahfoud Hadj-Mahammed
Keyword(s):  
Blood Glucose ◽  
Lipid Profile ◽  
Kidney Function ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Albino Rats ◽  
Liver And Kidney ◽  
Mean Blood Glucose

The aim of this study was to evaluate, for the first time, the antidiabetic effect of the alkaloids extract of Salvia chudaei Batt. & Trab. (Lamiaceae) on alloxan-induced diabetic rats. The alkaloids extract was prepared, and the in vitro inhibitory effect of key digesting enzymes related to postprandial hyperglycemia were determined. After acute toxicity test, the Swiss albino rats were induced with alloxan to get experimental diabetes animals. The fasting mean blood glucose, lipid profile, different liver and kidney function biomarkers and antioxidant biomarkers levels, after treatment for 30 days, diabetic untreated and diabetic rats treated with alkaloids extract were estimated. The alkaloids displayed remarkable in inhibiting ?-glucosidase (IC50 = 248.25?2.61 ?g/ml) than ?-amylase (IC50 = 262.96?9.64 ?g/ml) activities. In vivo, the results proved that alkaloids extract at dose of 500 mg/kg bw decreased significantly the blood glucose, lipid profile levels and improved the liver and kidney function biomarkers and increased the activities of antioxidant enzymes (superoxide dismutase and gluthatione reductase). This study demonstrates, that alkaloids are effective in inhibiting hyperglycemia and oxidative stress caused by diabetes.

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