4-Substituted-2-phenylquinazolines as inhibitors of BCRP

Juvale, Kapil; Wiese, Michael

doi:10.1016/j.bmcl.2012.08.024

Cited by 54 publications

(56 citation statements)

References 13 publications

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“…1). Our results indicate that prazosin is an inducer of BCRP, although some authors reported that prazosin is a BCRP inhibitor and substrate [24][25][26][27] . The reason for this contradiction may be differences in the materials used in the studies and in the employed doses of BCRP inhibitors and substrates.…”

Section: Discussioncontrasting

confidence: 47%

“…The inhibition of BCRP by prazosin may cause the activation of P-gp in the brain capillaries of mice. A compensatory relationship has been reported to exist between P-gp and BCRP, and P-gp has also been reported to be more prominent and inducible than BCRP at the BBB [33,34] Prazosin has been indicated to be only an inducer of P-gp [23][24][25][26][27] . In addition, many BCRP and P-gp substrates and modulators overlap [13,27,35] .…”

Section: Discussionmentioning

confidence: 99%

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Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

Traş¹,

Gül²,

Üney³

et al. 2016

Kafkas Univ Vet Fak Derg

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This study was conducted to determine whether the plasma and brain concentrations of AFB1 are affected by the modulation of P-gp and BCRP using zosuquidar (ZQR) and prazosin (PRZ), respectively. In this study, a total of 40 healthy adult male BALB/c mice (32±3.7 g) were used. The animals were randomly divided into 5 groups, with 8 animals per group. Group 1 was used for method validation. Group 2 (AF) received intraperitoneal AFB1 at a dose of 20 mg/kg of body weight. Groups 3 (AF+PRZ), 4 (AF+ZQR), and 5 (AF+PRZ+ZQR) received 20 mg/kg of AFB1 intraperitoneally 30 min after the intraperitoneal administration of prazosin (0.3 mg/kg), zosuquidar (25 mg/kg), and prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar), respectively. Six hours after the administration of AFB1, blood and brain samples were collected from the animals in Groups 2 to 5. AFB1 concentrations were determined using an HPLC system with fluorescence detection. Individual and simultaneous administration of prazosin and zosuquidar significantly reduced the brain concentrations of AFB1 in comparison to a single administration of AFB1 (P<0.05). The brain/plasma ratio of the AF group was higher than that of the other groups (AF+PRZ, AF+ZQR, and AF+PRZ+ZQR) (P<0.05). Inducers of transmembrane proteins, especially BCRP, can be life saving during acute AFB1 poisoning. Keywords: Aflatoxin B1, Brain, Drug transporter proteins, Modulation, Mice Aflatoksin B 1 'in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin EtkisiÖzet Çalışma, zosuquidar ve prazosin tarafından sırasıyla P-gp ve BCRP modülasyonunun AFB1'in plazma ve beyin konsantrasyonlarının etkileyip etkilemediğini belirlemek için gerçekleştirildi. Bu çalışmada, 40 adet sağlıklı, erkek BALB/c ırkı fare (32±3.7 g) kullanıldı. Hayvanlar her grupta 8 fare olacak şekilde rastgele 5 gruba ayrıldı. Grup 1, metod validasyon çalışmalarında kullanıldı. Grup 2 (AF)'ye AFB1 20 mg/kg dozda intraperitoneal yolla verildi. Grup 3 (AF+PRZ), 4 (AF+ZQR) ve 5 (AF+PRZ+ZQR)'e ise sırasıyla intraperitoneal yolla prazosin (0.3 mg/kg), zosuquidar (25 mg/kg) ve prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar) uygulamalarından 30 dk. sonra AFB1 20 mg/kg dozda intraperitoneal yolla uygulandı. Grup 2-5'de bulunan hayvanlardan AFB1 uygulamasından sonraki 6. saatte kan ve beyin örnekleri alındı. AFB1 düzeyleri fluoresans dedektör içeren HPLC sisteminde tayin edildi. Prazosin ve zosuquidarın tek ve eşzamanlı uygulanması AFB1'in beyin konsantrasyonlarında sadece AFB1 uygulamasına göre önemli oranda azalmaya neden oldu (P<0.05). AFB1 grubunda AFB1'in beyin/plazma oranı diğer gruplardan (AF+PRZ, AF+ZQR, and AF+PRZ+ZQR) önemli oranda daha yüksekti (P<0.05). Akut AFB1 zehirlenmelerinde özellikle BCRP gibi transmembran proteinlerin indüklenmesi hayatta kalma oranını artırabilir.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

Traş¹,

Gül²,

Üney³

et al. 2016

Kafkas Univ Vet Fak Derg

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“…Cyclosporine A (CsA) is a potent inhibitor of a number of uptake and efflux transporters, and represents the largest proportion of reported clinical transporter-mediated DDIs. It is known to inhibit OATP1B1 dmd.aspetjournals.org (Amundsen et al, 2010;Chang et al, 2013), OATP2B1 (Ho et al, 2006), BCRP (Xia et al, 2007), MRP1 (Juvale and Wiese, 2012), MRP2 (Lechner et al, 2010), and MRP3 (Kock et al, 2014) (Supplemental Table 2). CsA is the most potent inhibitor for OATPs, with K i , 0.1 mM (Ho et al, 2006;Amundsen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro

Zhang

Han

Putluru

et al. 2015

Drug Metabolism and Disposition

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Although the metabolism and disposition of diclofenac (DF) has been studied extensively, information regarding the plasma levels of its acyl-b-D-glucuronide (DF-AG), a major metabolite, in human subjects is limited. Therefore, DF-AG concentrations were determined in plasma (acidified blood derived) of six healthy volunteers following a single oral DF dose (50 mg). Levels of DF-AG in plasma were high, as reflected by a DF-AG/DF ratio of 0.62 6 0.21 (C max mean 6 S.D.) and 0.84 6 0.21 (area under the concentration-time curve mean 6 S.D.). Both DF and DF-AG were also studied as substrates of different human drug transporters in vitro. DF was identified as a substrate of organic anion transporter (OAT) 2 only (K m = 46.8 mM). In contrast, DF-AG was identified as a substrate of numerous OATs (K m = 8.6, 60.2, 103.9, and 112 mM for OAT2, OAT1, OAT4, and OAT3, respectively), two organic aniontransporting polypeptides (OATP1B1, K m = 34 mM; OATP2B1, K m = 105 mM), breast cancer resistance protein (K m = 152 mM), and two multidrug resistance proteins (MRP2, K m = 145 mM; MRP3, K m = 196 mM). It is concluded that the disposition of DF-AG, once formed, can be mediated by various candidate transporters known to be expressed in the kidney (basolateral, OAT1, OAT2, and OAT3; apical, MRP2, BCRP, and OAT4) and liver (canalicular, MRP2 and BCRP; basolateral, OATP1B1, OATP2B1, OAT2, and MRP3). DF-AG is unstable in plasma and undergoes conversion to parent DF. Therefore, caution is warranted when assessing renal and hepatic transporter-mediated drug-drug interactions with DF and DF-AG.

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“…The complete data set contains 135 molecules belonging to different structural classes, which were collected from 5 different sources after comprehensive literature search and cautious examinations of their assay conditions [49]–[53]. If there were more than one IC 50 value for a given molecule and they were in very close range, the averaged value was taken to assure better consistency.…”

Section: Methodsmentioning

confidence: 99%

In Silico Prediction of Inhibition of Promiscuous Breast Cancer Resistance Protein (BCRP/ABCG2)

et al. 2014

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BackgroundBreast cancer resistant protein has an essential role in active transport of endogenous substances and xenobiotics across extracellular and intracellular membranes along with P-glycoprotein. It also plays a major role in multiple drug resistance and permeation of blood-brain barrier. Therefore, it is of great importance to derive theoretical models to predict the inhibition of both transporters in the process of drug discovery and development. Hitherto, very limited BCRP inhibition predictive models have been proposed as compared with its P-gp counterpart.Methodology/Principal FindingsAn in silico BCRP inhibition model was developed in this study using the pharmacophore ensemble/support vector machine scheme to take into account the promiscuous nature of BCRP. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those molecules in the training set (n = 22, r 2 = 0.82, = 0.73, RMSE = 0.40, s = 0.24), test set (n = 97, q 2 = 0.75–0.89, RMSE = 0.31, s = 0.21), and outlier set (n = 16, q 2 = 0.72–0.91, RMSE = 0.29, s = 0.17). When subjected to a variety of statistical validations, the developed PhE/SVM model consistently met the most stringent criteria. A mock test by HIV protease inhibitors also asserted its predictivity.Conclusions/SignificanceIt was found that this accurate, fast, and robust PhE/SVM model can be employed to predict the BCRP inhibition of structurally diverse molecules that otherwise cannot be carried out by any other methods in a high-throughput fashion to design therapeutic agents with insignificant drug toxicity and unfavorable drug–drug interactions mediated by BCRP to enhance clinical efficacy and/or circumvent drug resistance.

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4-Substituted-2-phenylquinazolines as inhibitors of BCRP

Cited by 54 publications

References 13 publications

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

Aflatoksin B1’in Fare Beynine Geçişi Üzerine BCRP ve P-gp Modülatörlerinin Etkisi

Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro

In Silico Prediction of Inhibition of Promiscuous Breast Cancer Resistance Protein (BCRP/ABCG2)

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