ATP-binding cassette transporters in human heart failure

Solbach, Thomas F.; Paulus, Barbara; Weyand, Michael; Eschenhagen, Thomas; Zolk, Oliver; Fromm, Martin F.

doi:10.1007/s00210-008-0279-6

Cited by 46 publications

(34 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For rosiglitazone it has recently been demonstrated that it is a substrate of BCRP and can also inhibit this transporter with a half-maximal inhibitory concentration (IC) 50 value of 25 mol/l [16] . Moreover, troglitazone sulfate, the major metabolite of troglitazone, was identified as a BCRP substrate [17] , and troglitazone and rosiglitazone can induce BCRP [18] .…”

Section: Glitazones and Abc Transportersmentioning

confidence: 99%

Interaction of Thiazolidinediones (Glitazones) with the ATP-Binding Cassette Transporters P-Glycoprotein and Breast Cancer Resistance Protein

Weiß¹,

Sauer²,

Herzog³

et al. 2009

Pharmacology

View full text Add to dashboard Cite

Aims: Thiazolidinediones (glitazones) are frequently prescribed antidiabetic drugs commonly used in combination drug regimens. To evaluate the risk of drug-drug interactions, we therefore aimed to systematically investigate the inhibitory and inductive effects of all glitazones on 2 of the most relevant drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in vitro. Methods: The inhibition of P-gp and BCRP was assessed by fluorometric assays quantifying the increase in the intracellular concentration of fluorescent P-gp or BCRP substrates caused by their combination with the glitazones. The induction of mRNA expression was quantified by real-time RT-PCR after the treatment of HuH-7 cells with the respective compounds for 4 days. Results: Rosiglitazone and troglitazone significantly inhibited P-gp and BCRP function and induced mRNA expression of BCRP but not of P-gp. Pioglitazone, which exhibited very low solubility, could only be tested up to 0.5 μmol/l and did not provoke an effect in any of the assays. Conclusions: After comparison of the in vitro data and published clinical studies, it seems unlikely that the inhibition of BCRP and P-gp by rosiglitazone plays a role in the clinical situation. In contrast, BCRP induction by rosiglitazone might be of relevance in vivo, but has to be verified in dedicated clinical studies.

show abstract

Section: Glitazones and Abc Transportersmentioning

confidence: 99%

Interaction of Thiazolidinediones (Glitazones) with the ATP-Binding Cassette Transporters P-Glycoprotein and Breast Cancer Resistance Protein

Weiß¹,

Sauer²,

Herzog³

et al. 2009

Pharmacology

View full text Add to dashboard Cite

show abstract

“…Transport assays were performed as described previously (Solbach et al, 2008;Zolk et al, 2009 (Zolk et al, 2009). These potential inhibitors were selected based on previous publications suggesting them as substrates/inhibitors of OCT2 and/or on the presence of physicochemical characteristics generally associated with OCT2 substrates/ inhibitors, such as net positive charge at the amine nitrogen at physiological pH and molecular weight Ͻ500.…”

mentioning

confidence: 99%

Functional Characterization of the Human Organic Cation Transporter 2 Variant p.270Ala>Ser

Zolk

Solbach²,

König³

et al. 2009

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:The organic cation transporter 2 (OCT2, SLC22A2) plays an important role for renal drug elimination. Recent clinical studies indicate an impact of the frequent nonsynonymous c.808G>T (p.270Ala>Ser) polymorphism on renal clearance of metformin and the extent of the metformin-cimetidine interaction. The role of this polymorphism for renal disposition of endogenous compounds and drugs other than metformin has not been investigated. In addition, it is unclear whether the observed genotype dependence of an OCT2-mediated drug-drug interaction might occur also with other OCT inhibitors. To address these issues, we generated human embryonic kidney cells stably expressing wild-type OCT2 or the p.270Ala>Ser variant. No differences in protein expression levels and membrane incorporation pattern were observed between the two cell lines. The p.270Ala>Ser variant significantly impaired uptake kinetics of 1-methyl-4-phenylpyridinium, dopamine, norepinephrine, and propranolol. V max values were significantly reduced for uptake of all four compounds mediated by the p.270Ala>Ser variant compared with wild-type OCT2. In addition, a significant difference in the affinity to wild-type and mutant OCT2 was observed for dopamine (K m dopamine: 932 ؎ 77 versus 1285 ؎ 132 M). Moreover, out of a set of 27 compounds p.270Ala>Ser OCT2 was significantly less sensitive to inhibition by cimetidine, flurazepam, metformin, mexiletine, propranolol, and verapamil than wild-type OCT2 (e.g., for propranolol: IC 50 wild type versus p.270Ala>Ser 189 versus 895 M, P < 0.001). Our results indicate that the common OCT2 c.808G>T single nucleotide polymorphism significantly alters uptake of endogenous compounds and drugs. Moreover, for selected compounds the extent of OCT2-mediated drug interactions could depend on OCT2 c.808G>T genotype.

show abstract

“…BCRP is localized at endothelial cells and cardiomyocytes in heart (Meissner et al, 2006;Solbach et al, 2008). It is not clear whether this localization of BCRP in heart tissue is well reflected in the currently used tissue-slice method because the tissue surface might be exposed to the drug solution directly, and BCRP may not be able to exclude donepezil as efficiently as it would in its role as a tissue barrier transporter in intact tissue.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to P-glycoprotein, BCRP is also expressed in heart, mainly in capillary endothelial cells and cardiomyocytes (Meissner et al, 2006;Solbach et al, 2008;Higashikuni et al, 2010;Emmert et al, 2013), so BCRP is also a potential site of DDI. However, it has not been reported whether donepezil is a substrate of BCRP.…”

Section: Introductionmentioning

confidence: 99%

Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart

Takeuchi

Shinozaki

Nakanishi

et al. 2015

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Clinical reports indicate that cardiotoxicity due to donepezil can occur after coadministration with cilostazol. We speculated that the concentration of donepezil in heart tissue might be increased as a result of interaction with cilostazol at efflux transporters such as P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), which are expressed in many tissues including the heart, and our study tested this hypothesis. First, donepezil was confirmed to be a substrate of both BCRP and P-glycoprotein in transporter-transfected cells in vitro. Cilostazol inhibited BCRP and P-glycoprotein with half-inhibitory concentrations of 130 nM and 12.7 mM, respectively. Considering the clinically achievable unbound plasma concentration of cilostazol (about 200 nM), it is plausible that BCRP-mediated transport of donepezil would be affected by cilostazol in vivo. Indeed, in an in vivo rat study, we found that coadministration of cilostazol significantly increased the concentrations of donepezil in the heart and brain, where BCRP functions as a part of the blood-tissue barrier, whereas the plasma concentration of donepezil was unaffected. In addition, in vitro accumulation of donepezil in heart tissue slices of rats was significantly increased in the presence of cilostazol. These results indicate that donepezil-cilostazol interaction at BCRP may be clinically relevant in heart and brain tissues. In other words, the tissue distribution of drugs can be influenced by drug-drug interaction (DDI) at efflux transporters in certain tissues (local DDI) without any apparent change in plasma concentration (systemic DDI).

show abstract

ATP-binding cassette transporters in human heart failure

Cited by 46 publications

References 36 publications

Interaction of Thiazolidinediones (Glitazones) with the ATP-Binding Cassette Transporters P-Glycoprotein and Breast Cancer Resistance Protein

Interaction of Thiazolidinediones (Glitazones) with the ATP-Binding Cassette Transporters P-Glycoprotein and Breast Cancer Resistance Protein

Functional Characterization of the Human Organic Cation Transporter 2 Variant p.270Ala>Ser

Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart

Contact Info

Product

Resources

About