Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins

Pawarode, Attaphol; Shukla, Suneet; Minderman, Hans; Fricke, Stacy M.; Pinder, Elaine; O’Loughlin, Kieran L.; Ambudkar, Suresh V.; Baer, Maria R.

doi:10.1007/s00280-006-0357-8

Cited by 69 publications

(37 citation statements)

References 40 publications

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“…In fact, rapamycin and tacrolimus affected Pgp activity but they did not modulate Pgp function at pre-established doses. Similarly to what was previously reported by Pawarode and collegues (25) here, we show that CsA seems to be a broadspectrum MDR modulator impairing drug transport at the clinically achievable concentration of 2.5 µM, tacrolimus enhanced cellular drug uptake at 1 µM, but not at its clinically achievable concentration (0.1 µM). Rapamycin exerts the optimal effect of enhancing cellular drug uptake at 2.5 µM, but it was not effective at its clinically achievable concentration of 0.25 µM.…”

Section: Discussionsupporting

confidence: 65%

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Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function

et al. 2012

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-Purpose. P-glycoprotein (Pgp) is a member of the ABC-transporter family that transports substances across cellular membranes acting as an efflux pump extruding drugs out of the cells. Pgp plays a key role on the pharmacokinetics of several drugs. Herein, we have studied the effects of immunosuppressants on Pgp function, assessing rhodamine-123 (Rho123) uptake and efflux in different Tcell subsets. Methods. Different immunosuppressants such as Cyclosporine (CsA), Rapamycin (Rapa) and Tacrolimus (Tac) were used to assess the in vitro effect on Pgp function of main T-cell subsets among healthy volunteers. We measured Rho123 uptake, efflux and kinetic of extrusion in CD4 + and CD8 + subsets by flow cytometry. Antigen-specific memory T-cell responses were assessed by measuring T-cell proliferation and cytokine secretion using an allogeneic mixed lymphocyte reaction. Results. Rho123 uptake in groups treated with CsA and CsA+Rapa was significantly decreased compared to non-treated group and the other immunosupressants in both T cells subsets. Pgp activity was also reduced in CsA and CsA+Rapa compared to the other immunosupressants but it was only significant in the CsA group for CD8 + subset. Kinetic extrusion of Rho123 by Pgp in all groups was faster in CD8 + T cells. All immunosuppressants and the specific Pgp inhibitor PSC833 diminished antigen-primed T-cell proliferation, especially CD8 + T-cell subset. Conclusions. Our data indicate that small molecules immunosuppressants, especially CsA, inhibit Pgp activity and T-cell function being the CD8 + T cells more susceptible to this effect. These findings support the importance of Pgp when designing combined immunosuppressive regimens.

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Section: Discussionsupporting

confidence: 65%

“…Stimulated cells are exposed to allogeneic T-cell depleted lymphocytes. Drug concentrations were obtained from Pawarode et al choosing those in the upper level (25).…”

Section: Isolation Of Peripheral Blood Lymphocytesmentioning

confidence: 99%

Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function

et al. 2012

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“…Thus, this result implies that the autophagic machinery downstream of Beclin1-dependent induction was not a rate-limiting factor. On the other hand, rapamycin has been documented to modulate the transport function of Pglycoprotein, thereby acting as an agent that reverses the multidrugresistance phenotype (Arceci et al, 1992;Pawarode et al, 2007;Pop et al, 2009). Our results show that, although rapamycin inhibits P-glycoprotein expression in Ras-NIH3T3/Mdr cells, rapamycin has no effect on susceptibility to chemotherapeutic agents such as paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

“…Rapamycin (sirolimus), one of the main mTOR inhibitors used in clinical trials (Hartford and Ratain, 2007), has shown significant chemotherapeutic antitumor activity in various models (Kim et al, 2008;Weppler et al, 2007). Moreover, studies have established that rapamycin can downregulate and disable the P-glycoprotein pump (Pop et al, 2009) and enhance cellular drug uptake in cells overexpressing P-glycoprotein (Pawarode et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

Eum

Lee

2011

Molecules and Cells

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“…Thus, for a 70-kg subject, taking the volume of the gastrointestinal tract (3-5 l) into consideration (Egashira et al, 2004), the concentration of FK506 in the intestinal surface would be 1-3.5 mg/ml. In addition, a previous study (Pawarode et al, 2007) showed that 1 mM (about 0.8 mg/ml) of FK506 could enhance cellular drug uptake in cells overexpressing P-gp, multidrug resistance-associated protein 1 (MRP-1), or Breast cancer resistance-related protein (BCRP). Thus, to limit the inhibition effect of FK506 on P-gp activity and better mimic the clinical herb-drug interaction, the concentration of FK506 used in the transport experiment was set at 1 mg/ml (Qin et al, 2010b).…”

Section: Discussionmentioning

confidence: 99%

In Vivo to In Vitro Effects of Six Bioactive Lignans of Wuzhi Tablet (Schisandra Sphenanthera Extract) on the CYP3A/P-glycoprotein–Mediated Absorption and Metabolism of Tacrolimus

et al. 2013

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We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.

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Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins

Abstract: CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations.

Cited by 69 publications

References 40 publications

Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function

Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function

Targeting the Autophagy Pathway Using Ectopic Expression of Beclin 1 in Combination with Rapamycin in Drug-Resistant v-Ha-ras-Transformed NIH 3T3 Cells

In Vivo to In Vitro Effects of Six Bioactive Lignans of Wuzhi Tablet (Schisandra Sphenanthera Extract) on the CYP3A/P-glycoprotein–Mediated Absorption and Metabolism of Tacrolimus

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