Low levels of lymphocyte MDR1 gene expression during early renal transplantation in patients treated with tacrolimus

Becquemont, Laurent; Camus, M.; Kriaa, Faiçal; Barbu, Véronique; Charpentier, B; Jaillon, Patrice

doi:10.1111/j.1472-8206.2000.tb00020.x

Cited by 3 publications

(2 citation statements)

References 8 publications

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“…However, much higher intra-individual variability has also been described when phenotyping CYP2D6 activity, measured with the dextrometorphan/dextrorphan ratio over 3 months in healthy volunteers, which varied by approximately 50 '%, within individuals with maxinial fluctuations up to 136% [24]. Since lymphocyte P-gp seems to be more and more involved in the regulation of the pharmacological activity of different drugs, such as protease inhibitors [25] and immunosuppressive drugs [26], our data provide now important information to calculate the number of subjects to be included in future clinical trials investigating such a research area.…”

Section: Iiiter-~i I Dmentioning

confidence: 99%

Lymphocyte P‐glycoprotein expression and activity before and after rifampicin in man

Becquemont

Camus

Eschwège

et al. 2000

Fundamemntal Clinical Pharma

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It has recently been shown that P-glycoprotein (P-gp) is inducible by rifampicin in the human gut as shown in intestinal biopsies. The present study was performed in order to test the hypothesis that human peripheral lymphocytes can be used to assess such an inducibility. We also assessed inter- and intra-individual variability of P-gp expression and activity in peripheral lymphocytes. Blood samples from 13 healthy volunteers were collected 1.7, 14 and 19 days after inclusion. Rifampicin treatment (600 mg/day) was administered from day 15 to day 18. Lymphocyte P-gp expression was measured at the messenger RNA level by semi-quantitative RT-PCR and at the protein level by immunostaining flow cytometry. P-gp activity was determined by flow cytometry with rhodamine 123 efflux. Cytochrome P4503A4 (CYP3A4) inducibility was measured by comparing the urinary metabolic ratio of 6beta-hydroxycortisol/cortisol on day 14 and 19, Lymphocyte P-gp expression and activity was not induced by rifampicin, while it increased CYP3A4 activity from 5.0 +/- 4.0 to 22.9 +/- 16.6 (P < 0.001). There was a 3 - 4-fold inter-individual variability and a 3 - 44 % intra-individual variability of lymphocyte P-gp expression and activity. Peripheral lymphocytes are not an appropriate material to assess P-gp inducibility in humans. P-gp shows significant inter- and intra-individual variability in human lymphocytes.

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Section: Iiiter-~i I Dmentioning

confidence: 99%

Lymphocyte P‐glycoprotein expression and activity before and after rifampicin in man

Becquemont

Camus

Eschwège

et al. 2000

Fundamemntal Clinical Pharma

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“…Similarly, a decrease of the MDR1 expression in lymphocytes under renal transplant using tacrolimus as immunosuppressor has been observed. 51) Since the main function of Pgp in the hematoencephalic barrier is the extrusion of toxic metabolites back to the blood, 5) and the effect of tacrolimus is to decrease the expression and activity of this transporter, we postulate that the neurotoxic consequences of the use of this immunosuppressor are probably due to the endothelial accumulation and increased flux of this and other toxic molecules toward the brain. A genetic polymorphism in the MDR1 gene was recognized as a predictor factor for tacrolimus-induced neurotoxicity which may be explained by a reduced activity of Pgp and accumulation of tacrolimus into the brain.…”

Section: Discussionmentioning

confidence: 99%

Effect of Tacrolimus on Activity and Expression of P-Glycoprotein and ATP-Binding Cassette Transporter A5 (ABCA5) Proteins in Hematoencephalic Barrier Cells

Quezada

Garrido

González-Oyarzún

et al. 2008

Biological & Pharmaceutical Bulletin

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Tacrolimus (FK506) is widely used as an immunosuppressor in clinical practice; nonetheless a great part of its mechanisms of action and the processes triggering side effects remain unknown.1) A wide spectrum of adverse effects including neurotoxic, nephrotoxic, gastrointestinal, metabolic and hematological effects have been reported associated with tacrolimus.2) The major central nervous system (CNS) complications induced by this calcineurin inhibitor include headaches, altered mental status (AMS), seizures, cortical blindness, auditory and visual hallucinations, spasticity, paresis, and ataxia.3-5) The brain in many aspects differs from the other organs of the body; particularly because it is completely separated from the systemic circulation by the bloodbrain barrier (BBB) and haemato-cerebrospinal (HCE) barriers.6) P-glycoprotein (Pgp) is expressed in the luminal face of the BBB endothelial cells membrane. 7) A relevant role of Pgp in the extrusion of toxic metabolites from brain and the impairment of drugs to cross the hematoencephalic barrier has been determined using culture of brain capillary endothelial cells and Pgp knockout mice. [8][9][10][11][12][13] Substantial increases in the concentration of vinblastine, paclitaxel and doxorubicin were found in brains of knockout mice. These findings are probably due to the drug removal function exerted by this ATP-dependent efflux pump, also associated with the multidrug resistance (MDR) phenomenon.6) In humans, Pgp is encoded by two genes MDR1 and MDR3 the first being associated with MDR phenotype.14) The participation of MDR3 P-glycoprotein in multidrug resistance has been suggested by numerous studies; however, the rate of MDR3 P-glycoprotein-mediated transport is low for most drugs, and is not detectable due to its low expression rate. [15][16][17] The expression of other two ATP-binding cassette (ABC) type transporters, ABCA2 and ABCA5, was also detected in human brain capillary cells.18) ABCA2 was related to cholesterol and phospholipids remodelling function in neurons and glial cells, while ABCA5 lacks a recognized function in brain. 19) An effect of tacrolimus on multiple resistance to drugs was early observed in lymphoblastic leukemia cell lines leading to an increase in the intracellular accumulation and therefore cytotoxicity of chemotherapeutic agents. 20) In addition, other studies indicate that tacrolimus works as a substrate for Pgp.21) Although many of tacrolimus mechanisms of action and processes triggering neurotoxicity are still unknown, we proposed to explore the possibility that the side effects of tacrolimus at blood concentrations Ն30 ng/ml, could be linked to the functional blockade and variations in the expression levels of MDR proteins, such as MDR1, and probably ABCA5 in BBB cells. MATERIALS AND METHODS Cells CultureThe immortalized human brain microvascular endothelial cells, HBMEC, used in this study were kindly provided by Dr. Kwang Sik Kim (Johns Hopkins University, Baltimore, U.S.A.). The cells were grown in RPMI 1640 medium suppl...

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Pharmacogenetic differences and drug–drug interactions in immunosuppressive therapy

Warrington

Shaw²

2005

Expert Opinion on Drug Metabolism & Toxicology

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With the advent of new immunosuppressants and formulations, the elucidation of molecular targets and the evolution of therapeutic drug monitoring, the field of organ transplantation has witnessed significant reductions in acute rejection rates, prolonged graft survival and improved patient outcome. Nonetheless, challenges persist in the use of immunosuppressive medications. Marked interindividual variability remains in drug concentrations and drug response. As medications with narrow therapeutic indices, variations in immunosuppressant concentrations can result in acute toxicity or transplant rejection. Recent studies have begun to identify factors that contribute to this variability with the promise of tailoring immunosuppressive regimens to the individual patient. These advances have uncovered differences in genetic composition in drug-metabolising enzymes, drug transporters and drug targets. This review focuses on commonly used maintenance immunosuppressants (including cyclosporin, mycophenolate mofetil, tacrolimus, sirolimus, everolimus, azathioprine and corticosteroids), examines current studies on pharmacogenetic differences in drug-metabolising enzymes, drug transporters and drug targets and addresses common drug-drug interactions with immunosuppressant therapies. The potential role of drug-metabolising enzymes in contributing to these drug-drug interactions is briefly considered.

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Low levels of lymphocyte MDR1 gene expression during early renal transplantation in patients treated with tacrolimus

Cited by 3 publications

References 8 publications

Lymphocyte P‐glycoprotein expression and activity before and after rifampicin in man

Lymphocyte P‐glycoprotein expression and activity before and after rifampicin in man

Effect of Tacrolimus on Activity and Expression of P-Glycoprotein and ATP-Binding Cassette Transporter A5 (ABCA5) Proteins in Hematoencephalic Barrier Cells

Pharmacogenetic differences and drug–drug interactions in immunosuppressive therapy

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