Effect of ursodeoxycholic acid treatment on the expression and function of multidrug resistance-associated protein 2 in rat intestine

Yumoto, Ryoko; Hamada, Shota; Okada, Kiyoka; Kato, Yoshio; Ikehata, Mika; Nagai, Junya; Takano, Mikihisa

doi:10.1002/jps.21628

Cited by 7 publications

(3 citation statements)

References 30 publications

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“…UDCA feeding on mice stimulated the expression of mRNAs of hepatic, renal, and intestinal efflux transporters such as Mrp2 and Mrp3 [28]. Another study showed that the expression and function of intestinal Mrp2 were upregulated by oral administration of UDCA for six consecutive days in rats [29]. It has been demonstrated that UDCA could induce Mrps, detoxification, and the antioxidative system, along with Mrp-mediated efflux transport via the Nrf2 pathway in the liver [30].…”

mentioning

confidence: 99%

Ursodeoxycholic Acid Pretreatment Reduces Oral Bioavailability of the Multiple Drug Resistance-Associated Protein 2 Substrate Baicalin in Rats

Yan

et al. 2013

Planta Med

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Baicalin is a major bioactive component of Scutellaria baicalensis and a substrate of multiple drug resistance-associated protein 2. Expression of multiple drug resistance-associated protein 2 is regulated by NF-E2-related factor 2. The aim of this study was to explore whether ursodeoxycholic acid, an NF-E2-related factor 2 activator, could influence the oral bioavailability of baicalin. A single dose of baicalin (200 mg/kg) was given orally to rats pretreated with ursodeoxycholic acid (75 mg/kg and 150 mg/kg, per day, intragastrically) or normal saline (per day, intragastrically) for six consecutive days. The plasma concentration of baicalin was measured with the HPLC method. The result indicated that the oral bioavailability of baicalin was significantly and dose-dependently reduced in rats pretreated with ursodeoxycholic acid. Compared with control rats, the mean area under concentration-time curve of baicalin was reduced from 13.25 ± 0.24 mg/L h to 7.62 ± 0.15 mg/L h and 4.97 ± 0.21 mg/L h, and the C(max) value was decreased from 1.31 ± 0.03 mg/L to 0.62 ± 0.05 mg/L and 0.36 ± 0.04 mg/L in rats pretreated with ursodeoxycholic acid at doses of 75 mg/kg and 150 mg/kg, respectively, for six consecutive days. Hence, ursodeoxycholic acid treatment reduced the oral bioavailability of baicalin in rats, probably due to the enhanced efflux of baicalin from the intestine and liver by multiple drug resistance-associated protein 2.

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Ursodeoxycholic Acid Pretreatment Reduces Oral Bioavailability of the Multiple Drug Resistance-Associated Protein 2 Substrate Baicalin in Rats

Yan

et al. 2013

Planta Med

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“…In some cases, two different in‐vitro models have shown the same or different absorption for a similar substance [23] . However, frequently results from the everted intestinal sac model have been in agreement with in‐vivo findings [24–28] . The living system is more complex than in‐vitro models, in an in‐vitro condition there is probability of less or no enzymatic action.…”

Section: Introductionmentioning

confidence: 88%

Everted gut sac model as a tool in pharmaceutical research: limitations and applications

Alam

Al-Jenoobi

Al-Mohizea

2011

Journal of Pharmacy and Pharmacology

162

108

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Objectives This review discusses the limitations and applications of the everted gut sac model in studying drug absorption, metabolism, and interaction. Key findings The mechanism of drug absorption, interaction and the effect of factors such as age, sex, species, chronic therapy, and disease state on drug absorption have been summarized. The experimental conditions and their effects on the outcomes of trials have been discussed also. Summary The everted sac model is an efficient tool for studying in-vitro drug absorption mechanisms, intestinal metabolism of drugs, role of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine.

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“…The ex vivo everted rat intestinal sac model was used for studying BCRP mediated transport for each of the 5 compounds previously selected as BCRP nonsubstrates. , The main advantage of this technique with respect to in vitro assays is that the results obtained using ex vivo techniques often match those obtained from in vivo studies. − The BCRP is expressed in all segments of the rat small intestine from the duodenum and proximal jejunum to the distal jejunum and the ileocecal valve, including the ileum. The highest levels of BCRP expression are observed in the segment including the distal jejunum and ileum, and therefore this portion of the intestine was used to study the possible interaction of anticonvulsant drugs with the BCRP. , …”

Section: Materials and Methodsmentioning

confidence: 99%

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage

Gantner

Peroni

Morales

et al. 2017

J. Chem. Inf. Model.

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Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug-drug interactions.

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Effect of ursodeoxycholic acid treatment on the expression and function of multidrug resistance-associated protein 2 in rat intestine

Cited by 7 publications

References 30 publications

Ursodeoxycholic Acid Pretreatment Reduces Oral Bioavailability of the Multiple Drug Resistance-Associated Protein 2 Substrate Baicalin in Rats

Ursodeoxycholic Acid Pretreatment Reduces Oral Bioavailability of the Multiple Drug Resistance-Associated Protein 2 Substrate Baicalin in Rats

Everted gut sac model as a tool in pharmaceutical research: limitations and applications

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage

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