BCRP Transports Dipyridamole and is Inhibited by Calcium Channel Blockers

Zhang, Yi; Gupta, Anshul; Wang, Honggang; Zhou, Lin; Vethanayagam, R. Robert; Unadkat, Jashvant D.; Mao, Qingcheng

doi:10.1007/s11095-005-8384-4

Cited by 102 publications

(90 citation statements)

References 38 publications

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“…Digoxin is not a substrate for Bcrp [58], but other studies have indicated that the poor BBB permeability of digoxin is not explained by P-gp alone [11,38]. Verapamil has been used as a P-gp inhibitor in concentrations from 5 to 150 μM [23,[59][60][61], but it has also been shown to inhibit Mrp activity in concentrations of 5-10 μM [45,62] as well as Bcrp activity, although not in the concentration range applied here [63,64]. In our study, 50 μM verapamil lowered the efflux ratio of digoxin to 1.1, whereas the Bcrp inhibitor, Ko 143, had no effect on the digoxin transport indicating that the verapamil inhibition of A-L digoxin transport we observed was due to inhibition of P-gp or Mrp's.…”

Section: Efflux Transporter Activity In Bovine Blood-brain Barrier Momentioning

confidence: 98%

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms

Hersom

Kuhlmann

et al. 2014

AAPS J

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Abstract. Efflux transporters of the ATP-binding cassette superfamily including breast cancer resistance protein (Bcrp/Abcg2), P-glycoprotein (P-gp/Abcb1) and multidrug resistance-associated proteins (Mrp's/ Abcc's) are expressed in the blood-brain barrier (BBB). The aim of this study was to investigate if a bovine endothelial/rat astrocyte in vitro BBB co-culture model displayed polarized transport of known efflux transporter substrates. The co-culture model displayed low mannitol permeabilities of 0.95±0.1·10 H-etoposide revealed polarized transport favouring the brain-to-blood direction for all substrates. Steady state efflux ratios of 2.5±0.2 for digoxin, 4.4±0.5 for estrone-3-sulphate and 2.4±0.1 for etoposide were observed. These were reduced to 1.1±0.08, 1.4±0.2 and 1.5±0.1, by addition of verapamil (digoxin), Ko143 (estrone-3-sulphate) or zosuquidar+reversan (etoposide), respectively. Brain-toblood permeability of all substrates was investigated in the presence of the efflux transporter inhibitors verapamil, Ko143, zosuquidar, reversan and MK 571 alone or in combinations. Digoxin was mainly transported via P-gp, estrone-3-sulphate via Bcrp and Mrp's and etoposide via P-gp and Mrp's. The expression of P-gp, Bcrp and Mrp-1 was confirmed using immunocytochemistry. The findings indicate that P-gp, Bcrp and at least one isoform of Mrp are functionally expressed in our bovine/rat co-culture model and that the model is suitable for investigations of small molecule transport.KEY WORDS: blood-brain barrier; breast cancer resistance protein; multidrug resistance-associated protein; p-glycoprotein; polarized small molecule transport.

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Section: Efflux Transporter Activity In Bovine Blood-brain Barrier Momentioning

confidence: 98%

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Helms

Hersom

Kuhlmann

et al. 2014

AAPS J

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“…Chenodeoxycholate-3-sulfate [15] 131 Glycodeoxycholate [15] 2.0 Glycoursodeoxycholate [15] 4.1 Cholate [15,54] [15,54] 7.3/13 Deoxycholate [15,54] 5.2-13 Glycochenodeoxycholate [54] 2.0/2.9 Glychodeoxycholate [54] 2.4/5.4 Glycholate [54] 11/21 Taurochenodeoxycholate [15,54] 1.0-6.1 Taurocholate [15,54] 7.3-25 Taurodeoxycholate [15] 4.5-17 Taurourosdeoxycholate [15] 28 Ursodeoxycholate [15,54] 36 [60] Estrone [56] Bisantrene [67] Betamethasone [57] Riboflavin [68] Taurolithocholate sulfate [56] 37 a Cerivastatin [61] Cerivastain [61] 18 Uric acid [69] Vitamin K3 [ [70] Ciprofloxacin [71] Daunorubicin [56] 59 a Daunorubicin [67] Dexamethasone [57] Diclofenac [72] Diclofenac [72] 71-78 Dipyridamole [73] Digoxin [57] Doxorubicin [67,74] Dipyridamole [73] 6.4 a Enrofloxacin [75] Doxorubicin [56,76] Epirubicin [67] Fluvastatin [61] 5.4 Fluvastatin [61,62] Glibenclamide [77] 150 a Glibenclamide …”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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“…Both diltiazem and verapamil had a very weak effect on ABCG2/ BCRP. Zhang et al (19) reported that the inhibitory activity of nicardipine was strong and that of nifedipine was weak. In addition, diltiazem and verapamil were reported to hardly inhibit ABCG2/BCRP.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, in the case of calcium antagonists having a dihydropyridine structure, the side-chain of the dihydropyridine structure affected the inhibitory activity of ABCG2/BCRP, since the side-chains of calcium antagonists with strong inhibitory activity are larger in molecular weight and molecular surface area than those with weak inhibitory activity. Zhang et al (19) suggested that the side-chain of a heterocyclic compound affected the inhibitory activity of ABCG2/ BCRP. Consequently, if calcium antagonists are used as lead compounds, modifying the side-chain binding to the dihydropyridine structure may be a useful strategy for developing inhibitory activity against ABCG2/BCRP.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells

et al. 2011

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Abstract. The effects of 9 calcium antagonists on ABCG2/ BCRP-mediated resistance and transport were examined in HeLa and SN-38-resistant HeLa (HeLa/SN100) cells, overexpressing ABCG2/BCRP. Sensitivity to mitoxantrone, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly reversed by the coexistence of the calcium antagonists, except for diltiazem and verapamil. The accelerated transport activity of Hoechst33342, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly decreased by the presence of the calcium antagonists, except for diltiazem, nifedipine or verapamil, returning to the level of HeLa cells. The present study classifies the calcium antagonists into 3 categories: strong (benidipine, felodipine, nicardipine, nisoldipine and nitrendipine), moderate (amlodipine and nifedipine) and weak (diltiazem and verapamil) inhibitors of ABCG2/BCRP.

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BCRP Transports Dipyridamole and is Inhibited by Calcium Channel Blockers

Abstract: Dipyridamole and several dihydropyridines are effective BCRP inhibitors, but bepridil, diltiazem, and verapamil are not. We also identified a new BCRP substrate, dipyridamole.

Cited by 102 publications

References 38 publications

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

An Electrically Tight In Vitro Blood–Brain Barrier Model Displays Net Brain-to-Blood Efflux of Substrates for the ABC Transporters, P-gp, Bcrp and Mrp-1

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells

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