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

Llaudó, Inés; Cassis, Linda; Torrás, Joan; Bestard, Oriol; Franquesa, M.; Cerezo, Gema; Castaño, Esther; Pétriz, Jordi; Herrero‐Fresneda, Immaculada; Grinyó, Josep M.; Lloberas, Núria

doi:10.18433/j3g30b

Cited by 9 publications

(17 citation statements)

References 35 publications

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“…Since CsA induces greater hypertension than tacrolimus (36), besides via inhibition of calcineurin, CsA may cause hypertension also via another mechanism. Indeed, CsA, but not tacrolimus, also inhibits the ABCA1 transporter (25), which is responsible for Cho transport out of the cells (46). Our recent study (45) suggested that CsA causes hypertension by also stimulating the epithelial Na ϩ channel in distal nephron cells via ABCA1-dependent elevation of cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells

Liu

Song

et al. 2013

American Journal of Physiology-Renal Physiology

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We used mouse cortical collecting duct principal cells (mpkCCDc14 cell line) as a model to determine whether statins reduce the harmful effects of cyclosporine A (CsA) on the distal nephron. The data showed that treatment of cells with CsA increased transepithelial resistance and that the effect of CsA was abolished by lovastatin. Scanning ion conductance microscopy showed that CsA significantly increased the height of cellular protrusions near tight junctions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between cells. Western blot analysis and confocal microscopy showed that lovastatin also abolished CsA-induced elevation of both zonula occludens-1 and cholesterol in tight junctions. In contrast, a high concentration of CsA induced apoptosis, which was also attenuated by lovastatin, elevated intracellular ROS via activation of NADPH oxidase, and increased the expression of p47phox. Sustained treatment of cells with lovastatin also induced significant apoptosis, which was attenuated by CsA, but did not elevate intracellular ROS. These results indicate that both CsA and lovastatin are harmful to principal cells of the distal tubule, but via ROS-dependent and ROS-independent apoptotic pathways, respectively, and that they counteract probably via mobilization of cellular cholesterol levels.

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Section: Discussionmentioning

confidence: 99%

Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells

Liu

Song

et al. 2013

American Journal of Physiology-Renal Physiology

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“…[49] In this context, patients (high pumpers) treated with low doses of CsA would show lower drug exposure and this could affect MPA AUC exposure. [17,49] …”

Section: Discussionmentioning

confidence: 99%

“…These immunosuppressants act as substrates and/or inhibitors of Pgp, alter the bioavailability of many concomitantly used drugs, and are potential inducers of drug–drug interactions. [17] …”

Section: Introductionmentioning

confidence: 99%

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

et al. 2017

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The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0–12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0–12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0–12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.

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“…Additionally, the difference in P-gp functional activity between GCs-responsive and GCs-nonresponsive patients with ITP was significant only in CD8 + T cells. Llaudó et al [37] also indicated that P-gp inhibitors diminished P-gp activity and T-cell function, especially on CD8 + T cells subsets. These results suggested that CD8 + T cells might contain the main target sites of P-gp in ITP.…”

Section: Discussionmentioning

confidence: 98%

Effects of the multidrug resistance-1 gene on drug resistance in primary immune thrombocytopenia

Liu

Zhang

et al. 2016

Autoimmunity

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Primary immune thrombocytopenia (ITP) is an autoimmune disorder that is characterized by low platelet count. Glucocorticoids (GCs) resistance is a great challenge in the treatment of ITP. P-glycoprotein (P-gp) is a widely studied protein, which is associated with drug resistance. However, in ITP, the functional activity and immune regulation mechanism of P-gp remain uncertain. In this study, we evaluated the expression and functional activity of P-gp in different lymphocyte subsets, explored the correlation between P-gp function and GCs resistance and investigated the role of P-gp in ITP pathogenesis. Results indicated that the functional activity and mRNA level of P-gp were significantly higher in GCs-nonresponsive patients than in GCs-responsive patients with ITP. However, these differences in P-gp were only significant in CD8 T cells. P-gp function was related to disease activity rather than GCs therapy. P-gp was involved in secreting granzyme B and perforin, maintaining autoreactive lymphocytes survival and enhancing autologous platelets lysis in ITP. In conclusion, over-functional P-gp might play an important role in the pathogenesis of ITP and induce GCs resistance in nonresponsive ITP patients. The blockage of P-gp could be a promising therapeutic approach for GCs-resistant patients with ITP.

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

Cited by 9 publications

References 35 publications

Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells

Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells

Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

Effects of the multidrug resistance-1 gene on drug resistance in primary immune thrombocytopenia

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