Expression of Calcineurin Activity after Lung Transplantation: A 2-Year Follow-Up

Sanquer, Sylvia; Amrein, C.; Grenet, Dominique; Guillemain, R.; Philippe, B.; Boussaud, V.; Herry, Laurence; Lena, Celine; Diouf, Alphonsine; Paunet, Michelle; Billaud, Éliane; Loriaux, Françoise; Jaı̈s, Jean-Philippe; Barouki, Robert; Stern, M.

doi:10.1371/journal.pone.0059634

Cited by 18 publications

(13 citation statements)

References 35 publications

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“…Therefore, using TAC intra-PBMC concentration would be a surrogate marker easier to implement in clinical practice. Among pharmacodynamic parameters reflecting TAC effect, the clinical utility of CaN activity measurement was reported by several authors [8,36,37] and an important interpatient variability was described in their works as in our study. Such a variability as well as the imperfect correlation observed with the intracellular concentration (r = À0.5) could be explained by wild differences in the relative level of FK binding protein (FKBP) isoforms in PBMC from different patients [38].…”

Section: Discussionsupporting

confidence: 63%

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters

Tron

Allard

Petitcollin

et al. 2018

Fundamemntal Clinical Pharma

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Measuring tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) could better reflect the drug effect on its target (calcineurin (CaN) in lymphocytes) than whole blood concentrations. Mechanisms influencing TAC diffusion into PBMC are not well characterized. This work aimed at describing, ex vivo, TAC diffusion kinetics into PBMC and investigating the contribution of membrane transporters to regulate TAC intracellular concentration as well as the impact on CaN activity. PBMCs were incubated with TAC for 5 min to 4 h and under several experimental conditions: 37 °C (physiological conditions), 4 °C (inhibition of influx and efflux active transport), 37 °C + transporter inhibitors (verapamil, carvedilol, and probenecid and bromosulfophthalein, respectively, inhibitors of P-gp, OAT, and OATP). TAC concentration and CaN activity were measured in PBMC using liquid chromatography coupled with mass spectrometry. TAC intra-PBMC concentration was maximal after 1 h of incubation. Mean TAC PMBC concentrations were significantly lower in samples incubated at 4 °C compared to the 37 °C groups. Addition of verapamil slightly increased TAC accumulation in PBMC while other inhibitors had no effect. A significant correlation was found between TAC intra-PBMC concentration and the level of inhibition of CaN. Using an ex vivo cellular model, these results suggest that P-gp is involved in the drug efflux from PBMC while influx active transporters likely to regulate TAC intra-PBMC disposition remain to be identified. TAC concentration in PBMC is correlated with its pharmacodynamic effect. Then, TAC intra-PBMC concentration appears to be a promising biomarker to refine TAC therapeutic drug monitoring.

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Section: Discussionsupporting

confidence: 63%

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters

Tron

Allard

Petitcollin

et al. 2018

Fundamemntal Clinical Pharma

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“…Different investigations have reported that liver transplant recipients experiencing ACR exhibit higher calcineurin activity than those without a rejection episode, suggesting a lower pharmacological impact of TAC [16][17][18]. This increased calcineurin activity within a graft rejection episode has also been confirmed in patients after lung [35], renal [36] or liver transplantation [18]. The question raised…”

Section: Capron Et Al Have Recently Documented That Low Tac Concentrmentioning

confidence: 92%

Pharmacokinetics and pharmacodynamics of tacrolimus in liver transplant recipients: inside the white blood cells

Lemaître

Blanchet

Latournerie

et al. 2015

Clinical Biochemistry

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Drug monitoring of TAC intracellular concentrations and determination of the calcineurin activity are among future potential biomarkers of acute rejection in transplant recipients. A better knowledge of the relationship between TAC whole blood and intracellular concentrations and calcineurin activity appears necessary before planning clinical trials to evaluate their potential interest as predictive biomarkers.

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“…acute cellular rejection [24][25][26]. A few studies, conducted in liver transplantation, described the pharmacokinetic-pharmacodynamic relationship of TAC by studying the link between whole blood concentrations and CaN activity in PBMC [27][28][29].…”

Section: Plos Onementioning

confidence: 99%

Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

et al. 2020

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Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC 50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.

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Expression of Calcineurin Activity after Lung Transplantation: A 2-Year Follow-Up

Cited by 18 publications

References 35 publications

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters

Pharmacokinetics and pharmacodynamics of tacrolimus in liver transplant recipients: inside the white blood cells

Pharmacogenetic—Whole blood and intracellular pharmacokinetic—Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients

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