Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study

Rayar, Michel; Tron, Camille; Locher, Clara; Chébaro, Alexandre; Beaurepaire, Jean-Marie; Blondeau, Marc; Cusumano, Caterina; Bardou-Jacquet, Édouard; Houssel‐Debry, Pauline; Camus, Christophe; Petitcollin, Antoine; Verdier, M. C.; Lakéhal, M.; Desfourneaux, Véronique; Sulpice, Laurent; Meunier, Bernard; Boudjéma, Karim; Lemaître, F.

doi:10.1016/j.clinthera.2018.10.015

Cited by 7 publications

(5 citation statements)

References 13 publications

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“…In a study published in liver transplant patients, Capron et al have shown that intra-biopsy concentrations of tacrolimus were correlated with the onset of rejection and its severity 6 . Additionally, our team correlated tacrolimus concentration in bile (peri-tissular fluid) with neurologic side-effects in liver transplant recipients as well 14 . Intratissular ISD measurement can thus be used as an exploratory tool to evaluate drugs effects and represent a potential complementary test to usual whole blood concentration determination.…”

Section: Discussionmentioning

confidence: 99%

A simple and fast liquid chromatography tandem mass spectrometry method to determine cyclosporine A concentrations in endomyocardial biopsies

Tron

Coste

Lalanne

et al. 2021

Journal of Pharmaceutical and Biomedical Analysis

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Measuring cyclosporine A (CsA), an immunosuppressive drug used to prevent heart transplant rejection, concentrations in myocardial biopsies might be more informative than its measurement in whole blood. Therefore, a fast, accurate and reproductive method to determine CsA concentration in this complex matrix is needed. We report the validation of a liquid chromatography tandem mass spectrometry method to measure CsA concentration in heart parenchyma, applicable to everyday practice. The method was found to be precise, accurate, reproducible, specific of CsA, and without any matrix effect or carry-over. The lower limit of quantification was 50 pg of CsA in myocardium. The method was linear up to 2000 pg of CsA in myocardium. Samples were found stable for one year at -80°C. At last, 40 drugs which could be prescribed to heart transplant recipients were tested with the method and showed no interference with CsA signal. The method was suitable to quantify CsA in endomyocardial biopsies from heart transplanted patients. This method allows designing clinical studies aiming at exploring the relationship between CsA intra-graft concentrations and outcome.Abbreviations: acute rejection (AR); adverse events (AE); centre de ressources biologiques (CRB); coefficient of variation (CV); cyclosporine A (CsA); European Medicine Agency (EMA); endomyocardial biopsies (EMB); heart transplantation (HT); high performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS); immunosuppressive drugs (ISD); interleukine-2 (IL-2); internal standard (IS); lower limit of quantification (LLOQ); mass spectrometry (MS); matrix factor (MF); peripheral blood mononuclear cells (PBMC); quality controls (QC); relative error (RE); standards (Std); therapeutic drug monitoring (TDM).

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Section: Discussionmentioning

confidence: 99%

A simple and fast liquid chromatography tandem mass spectrometry method to determine cyclosporine A concentrations in endomyocardial biopsies

Tron

Coste

Lalanne

et al. 2021

Journal of Pharmaceutical and Biomedical Analysis

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“…Although the metabolic phenoconversion induced by inflammation may not be associated with short-term clinical signs of toxicity for other drugs (tacrolimus, voriconazole, risperidone), acute inflammation can also contribute to the increase in intra-individual variability of drugs that are CYP substrates, possibly leading to deleterious long-term consequences. For example, increased intra-individual variability of the tacrolimus blood Cmin is associated with a poorer clinical outcome in hepatic transplant patients ( Rayar et al, 2018 ). Moreover, it should also be kept in mind that total plasma drug concentration (free concentration + bound concentration) are measured during TDM or in most clinical studies (see Table 3 ).…”

Section: How To Integrate the Inflammatory Status In Personalized Medmentioning

confidence: 99%

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

Stanke‐Labesque

Gautier-Veyret

Chhun

et al. 2020

Pharmacology & Therapeutics

131

147

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Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.

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“…31 However, this finding was not confirmed in other studies in kidney and liver transplantation. 23,[32][33][34][35] One possible explanation for these conflicting findings may be that the PBMC fraction consists of many different immune cell subsets that have different roles in allorecognition and rejection. In a previous study, the intracellular concentration of tacrolimus was measured in CD3 + T-lymphocytes and CD14 + monocytes.…”

Section: Discussionmentioning

confidence: 99%

P-glycoprotein, FK-binding Protein-12, and the Intracellular Tacrolimus Concentration in T-lymphocytes and Monocytes of Kidney Transplant Recipients

et al. 2022

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Background . Transplant recipients may develop rejection despite having adequate tacrolimus whole blood predose concentrations (C0). The intra-immune cellular concentration is potentially a better target than C0. However, little is known regarding intracellular tacrolimus concentration in T-lymphocytes and monocytes. We investigated the tacrolimus concentrations in both cell types and their relation with the expression and activity of FK-binding protein (FKBP)-12 and P-glycoprotein (P-gp). Methods . T-lymphocytes and monocytes were isolated from kidney transplant recipients followed by intracellular tacrolimus concentration measurement. FKBP-12 and P-gp were quantified with Western blot, flow cytometry, and the Rhodamine-123 assay. Interleukin-2 and interferon-γ in T-lymphocytes were measured to quantify the effect of tacrolimus. Results . Tacrolimus concentration in T-lymphocytes was lower than in monocytes (15.3 [8.5–33.4] versus 131.0 [73.5–225.1] pg/million cells; P < 0.001). The activity of P-gp (measured by Rhodamine-123 assay) was higher in T-lymphocytes than in monocytes. Flow cytometry demonstrated a higher expression of P-gp (normalized mean fluorescence intensity 1.5 [1.2–1.7] versus 1.2 [1.1–1.4]; P = 0.012) and a lower expression of FKBP-12 (normalized mean fluorescence intensity 1.3 [1.2–1.7] versus 1.5 [1.4–2.0]; P = 0.011) in T-lymphocytes than monocytes. Western blot confirmed these observations. The addition of verapamil, a P-gp inhibitor, resulted in a 2-fold higher intra-T-cell tacrolimus concentration. This was accompanied by a significantly fewer cytokine-producing cells. Conclusions . T-lymphocytes have a higher activity of P-gp and lower concentration of the FKBP-12 compared with monocytes. This explains the relatively lower tacrolimus concentration in T-lymphocytes. The addition of verapamil prevents loss of intracellular tacrolimus during the cell isolation process and is required to ensure adequate intracellular concentration measurement.

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Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study

Cited by 7 publications

References 13 publications

A simple and fast liquid chromatography tandem mass spectrometry method to determine cyclosporine A concentrations in endomyocardial biopsies

A simple and fast liquid chromatography tandem mass spectrometry method to determine cyclosporine A concentrations in endomyocardial biopsies

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment

P-glycoprotein, FK-binding Protein-12, and the Intracellular Tacrolimus Concentration in T-lymphocytes and Monocytes of Kidney Transplant Recipients

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