Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4

El-Sheikh, Azza A. K.; Greupink, Rick; Wortelboer, Heleen M.; Heuvel, Jeroen J. M. W. van den; Schreurs, Marieke; Koenderink, Jan B.; Masereeuw, Rosalinde; Rüssel, Frans G. M.

doi:10.1016/j.trsl.2013.08.003

Cited by 64 publications

(45 citation statements)

References 54 publications

(62 reference statements)

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“…22,24 In vitro, MRP4 expression cells uptake MTX and confer MTX resistance. 13,25,26 Our results differ from these studies, because the patients were treated with low doses of MTX (25 mg m − 2 per week orally) and physician commonly reduced MTX dose after 6-MP adjustment. Further studies are needed to clarify MRP4 variant influence on pharmacokinetics on low-dose oral MTX therapy.…”

Section: Discussioncontrasting

confidence: 64%

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

et al. 2014

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Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30 − 50 mg m − 2 in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m − 2 , P = 0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

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Section: Discussioncontrasting

confidence: 64%

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

et al. 2014

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“…In summary, enalaprilat, the active metabolite of enalapril, is effluxed across the basolateral membrane of hepatocytes by MRP4. MRP4 transport may be inhibited by concomitantly administered drugs (Hasegawa et al, 2007;El-Sheikh et al, 2013;Fukuda et al, 2013). This work highlights the significance of active basolateral efflux in the therapeutic efficacy of active metabolites derived in the liver and excreted into the systemic circulation.…”

Section: Kinetic Parametersmentioning

confidence: 82%

Role of Multidrug Resistance–Associated Protein 4 in the Basolateral Efflux of Hepatically Derived Enalaprilat

et al. 2014

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Hepatic uptake and efflux transporters govern the systemic and hepatic exposure of many drugs and metabolites. Enalapril is a pharmacologically inactive prodrug of enalaprilat. Following oral administration, enalapril is converted to enalaprilat in hepatocytes and undergoes translocation into the systemic circulation to exert its pharmacologic effect by inhibiting angiotensin-converting enzyme. Although the transport proteins governing hepatic uptake of enalapril and the biliary excretion of enalapril and enalaprilat are well established, it remains unknown how hepatically derived enalaprilat translocates across the basolateral membrane into the systemic circulation. In this study, the role of ATP-binding cassette transporters in the hepatic basolateral efflux of enalaprilat was investigated using membrane vesicles. ATP-dependent uptake of enalaprilat into vesicles expressing multidrug resistance-associated protein (MRP) 4 was significantly greater (∼3.8-fold) than in control vesicles. In contrast, enalaprilat was not transported to a significant extent by MRP3, and enalapril was not transported by either MRP3 or MRP4. The functional importance of MRP4 in the basolateral excretion of derived enalaprilat was evaluated using a novel basolateral efflux protocol developed in human sandwich-cultured hepatocytes. Under normal culture conditions, the mean intrinsic basolateral efflux clearance (CL int,basolateral ) of enalaprilat was 0.026 6 0.012 ml/min; enalaprilat CL int,basolateral was significantly reduced to 0.009 6 0.009 ml/min by pretreatment with the pan-MRP inhibitor MK-571. Results suggest that hepatically derived enalaprilat is excreted across the hepatic basolateral membrane by MRP4. Changes in MRP4-mediated basolateral efflux may alter the systemic concentrations of this active metabolite, and potentially the efficacy of enalapril.

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“…Another possible explanation for the similar accumulation of Hg 2+ in the OSOM of SD and bcrp −/− rats is that the activity, but not the number, of Mrp2 transporters is increased in bcrp −/− rats in order to compensate for the absence of Bcrp. Indeed, Mrp2 activity has been shown to be enhanced (without an increase in protein) by the presence of certain substrates (El-Sheikh et al , 2013; Guyot et al , 2014). A third possible explanation is that additional, yet unknown, transport mechanisms for Hg 2+ are present in S3 segments.…”

Section: 0 Discussionmentioning

confidence: 99%

Toxicological significance of renal Bcrp: Another potential transporter in the elimination of mercuric ions from proximal tubular cells

Bridges

Zalups

Joshee

2015

Toxicology and Applied Pharmacology

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Secretion of inorganic mercury (Hg2+) from proximal tubular cells into the tubular lumen has been shown to involve the multidrug resistance-associated protein 2 (Mrp2). Considering similarities in localization and substrate specificity between Mrp2 and the breast cancer resistance protein (Bcrp), we hypothesize that Bcrp may also play a role in the proximal tubular secretion of mercuric species. In order to test this hypothesis, the uptake of Hg2+ was examined initially using inside-out membrane vesicles containing Bcrp. The results of these studies suggest that Bcrp may be capable of transporting certain conjugates of Hg2+. To further characterize the role of Bcrp in the handling of mercuric ions and in the induction of Hg2+-induced nephropathy, Sprague-Dawley and Bcrp knockout (bcrp−/−) rats were exposed intravenously to a non-nephrotoxic (0.5 μmol • kg−1), a moderately nephrotoxic (1.5 μmol • kg−1) or a significantly nephrotoxic (2.0 μmol • kg−1) dose of HgCl2. In general, the accumulation of Hg2+ was greater in organs of bcrp−/− rats than in Sprague-Dawley rats, suggesting that Bcrp may play a role in the export of Hg2+ from target cells. Within the kidney, cellular injury and necrosis was more severe in bcrp−/− rats than in controls. The pattern of necrosis, which was localized in the inner cortex and the outer stripe of the outer medulla was significantly different from that observed in Mrp2-deficient animals. These findings suggest that Bcrp may be involved in the cellular export of select mercuric species and that its role in this export may differ from that of Mrp2.

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Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4

Cited by 64 publications

References 54 publications

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

Role of Multidrug Resistance–Associated Protein 4 in the Basolateral Efflux of Hepatically Derived Enalaprilat

Toxicological significance of renal Bcrp: Another potential transporter in the elimination of mercuric ions from proximal tubular cells

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