Original ArticleInteraction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4
Section snippets
Materials and Methods
We conformed to all relevant guidelines for human and animal research and adhered to national guidelines and laws for working with genetically modified organisms when overexpressing recombinant human proteins in vitro.
[3H]-MTX transport and inhibition in OAT1-expressing cells
Fig 1A shows that [3H]-MTX uptake was increased in the OAT1-expressing cells compared with controls. Moreover, MTX uptake in HEK-OAT1 cells could be inhibited by the prototypical OAT inhibitor probenecid (Fig 1, B). Transporter-mediated uptake of [3H]-MTX over time in HEK-OAT1 cells is presented in Fig 1, C and was linear up to 5 minutes.
Next, HEK-OAT1 cells were incubated with 0.5 μM [3H]-MTX in the presence or absence of 10 μM of different immunosuppressants for 5 minutes. Our results (Fig 1,
Discussion
We have previously investigated the role of MRP2 and MRP4 in the clinically reported interaction between MTX and nonsteroidal anti-inflammatory drugs, and from these results we suggested that both transporters have allosteric binding sites.14 Here, we studied the interaction of different immunosuppressant drugs with [3H]-MTX, which is a common substrate of renal basolateral OAT1 and OAT3,16 as well as apical efflux MRP217 and MRP418 transporters. Our results show that several immunosuppressants
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2022, Drug Discovery TodayCitation Excerpt :Consequently, to generate a CsA derivative with more-potent CypA inhibition but a lesser immunosuppressive effect, a modified CsA has been designed with substitutions in the side chains P4, P5 and P6 and a change to the P3 side chain to increase its binding to CypA. In addition to its potential CypA inhibition activity and the related immunosuppressive effect, CsA was also found to remarkably inhibit several endogenous transporters, including organic anion transporting receptors (OATP1B1 and OATP1B3),108 bile salt export pump, multidrug resistance protein 1 (MDR1; also named ABCB1 or P-gp)109 and MDR2.110 From 1984 to 1997, CsA derivatives were chemically synthesized and evaluated for their ability to inhibit CypA, and were subjected to detailed SAR analyses by several research groups.
Multidrug resistance-associated protein 4 in pharmacology: Overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics
2019, Life SciencesCitation Excerpt :Some studies also suffer from lack of power. For example, MTX is transported by MRP4 and MRP2 with different affinities [58]. The reduced function of one transporter due to a genetic variation (or to the inhibition through drug-drug interaction) can be compensated by overexpression of the second transporter.
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2019, European Journal of Pharmaceutical SciencesCitation Excerpt :OATs located in kidney are important determinants of kidney exposure and potency of substrate drugs, like diuretics and angiotensin-converting enzyme inhibitors (Morrissey et al., 2013). On the other hand, OATs-mediate accumulation of toxics, such as methotrexate and aristolochic acid, resulted in nephrotoxicity (El-Sheikh et al., 2013; Xue et al., 2011). Therefore, it has been recommended evaluating the transport property during drug development by US Food and Drug Administration (FDA).
Conflict of Interest: All authors have read the journal’s policy on disclosure of potential conflicts of interest and have none to declare.
This work was supported in part by a scholarship granted by the Egyptian Ministry of Higher Education to A. A. K. El-Sheikh.
A. A. K. El-Sheikh and R. Greupink contributed equally to this work. A. A. K. El-Sheikh, R. Greupink, J. B. Koenderink, R. Masereeuw, and F. G. M. Russel participated in research design; A. A. K. El-Sheikh, J. J. M. W. van den Heuvel, R. Greupink, and M. Schreurs conducted experiments; H. M. Wortelboer contributed organic anion transporter 3 overexpressing cells; A. A. K. El-Sheikh and R. Greupink performed data analysis; and A. A. K. El-Sheikh, R. Greupink, J. B. Koenderink, R. Masereeuw, and F. G. M. Russel Wrote or contributed to the writing of the manuscript.
This work was performed in part during the PhD research of A. A. K. El-Sheikh, conducted at the Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Netherlands, and supervised by J. B. Koenderink, R. Masereeuw, and F. G. M. Russel. The thesis was titled “Renal Transport and Drug Interactions of Immunosuppressants,” printed by Printpartners Ipskamp, Enschede, Netherlands, 2008 (ISBN: 978-90-9023458-8).