Comparison of the Temporal Profile of Calcineurin Inhibition by Cyclosporine and Tacrolimus in Renal Transplant Patients

doi:10.1016/j.transproceed.2005.02.071

Transplantation Proceedings

Volume 37, Issue 4, May 2005, Pages 1736-1738

https://doi.org/10.1016/j.transproceed.2005.02.071 Get rights and content

Abstract

Calcineurin phosphatase (CaN) activity has been the focus of several recent studies on renal transplant patients as the calcineurin inhibitors tacrolimus (FK) and cyclosporine (CsA) are still the cornerstone in the immunosuppressive treatment. The aim of this study was to compare the temporal inhibition profiles of CaN using CsA or FK in two groups of renal transplant patients. Nineteen tacrolimus-treated and 10 cyclosporine-treated renal transplant patients had blood samples drawn before and at 1, 2, 3, 4, and 6 hours after ingestion of drug. CaN activity was measured as the release of ³²P from a previously phosphorylated peptide and radioactivity quantitated by liquid scintillation counting. Results were expressed as units CaN. Blood concentrations of tacrolimus were determined with an IMx method and of CsA with an EMIT assay. FK-treated patients showed maximal inhibition of CaN activity at 1 to 3 hours, returning to the predose level 4 hours after drug intake. CsA-treated patients showed a gradual decrease in CaN activity with a nadir after 3 hours, failing to return to predose levels during the observation period. Both groups showed a significant rise in drug blood concentrations. To conclude, we have demonstrated that two widely used immunosuppressants, CsA and FK, show different CaN inhibitory profiles in renal transplant patients.

Section snippets

Patients

This study evaluated 29 renal transplant patients, including nine males and one female who were treated with cyclosporine, versus 11 males and eight females treated with tacrolimus. These regimens also included prednisolone and azathioprine. The mean dose of tacrolimus was 14 mg/day, and the mean CsA dose was 565 mg/day. The median time from transplantation to inclusion in the study was 14 days for patients treated with FK and 9.5 days for the CsA-treated patients. The mean ages were 41.7 ±

Results

Figure 1A shows the relation of FK drug concentrations to CaN activities. We found an inverse relationship between drug concentration and CaN activity. The FK concentration reached its maximum within 2 hours after drug ingestion, remaining significantly elevated compared to predose levels for the entire observational period (T: 1, 2, 3, 4, and 6; P < .001). CaN was inhibited maximally at 1 to 3 hours postdose, returning to predose levels at 4 hours after drug intake. At T: 1, 2, and 3, CaN

Discussion

We demonstrated that CsA and FK show different CaN inhibitory profiles in renal transplant patients. The FK-treated patients showed a fast maximal inhibition of CaN with enzyme activity returning to the predose level at 4 hours after drug ingestion. On the other hand, CsA-treated patients showed a more gradual decrease in CaN activity, reaching a minimum at 3 hours; the enzyme activity did not return to predose level within the observational period.

This study had an observational period of 6

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Cited by (10)

Measurement of calcineurin activity in peripheral blood mononuclear cells by ultra-high performance liquid chromatography-tandem mass spectrometry. Renal transplant recipients application (pharmacodynamic monitoring)
2019, Clinica Chimica Acta
Citation Excerpt :
Different clinical studies have demonstrated that CNI diminished CNA after drug intake in solid organ transplantation measured in whole blood, leukocytes and peripheral blood mononuclear cells (PBMCs) [8–10]. Transplant patients receiving cyclosporine (CsA) showed less CNA with maximum inhibition after 2 h of drug intake [8,11–15]. In contrast, patients with TAC treatment diminished CNA after 1 h after oral administration [9,12,14,16,17].
Therapeutic drug monitoring of calcineurin inhibitor, tacrolimus (TAC), is routinely used in post-transplantation. Currently, measurement of calcineurin activity has been proposed as a promising clinical tool to evaluate efficacy and to optimize drug dosing. The main aim of our study was to develop a method to measure phosphatase calcineurin activity (CNA) in peripheral blood mononuclear cells (PBMCs) by ultra-high performance liquid chromatography-tandem mass spectrometry and to validate it following FDA and EMA guidelines.
This methodology is based on monitoring the Ca²⁺-dependent dephosphorylation of a phosphopeptide substrate. CNA was evaluated in 5 healthy volunteers and in 5 renal transplant patients receiving twice-daily formulation of TAC before drug intake. Moreover, we studied pharmacodynamic effect of TAC and blood concentrations of TAC in different drug dose intervals (0, 1, 3, 6 and 12 h).
Our results showed linearity in the range 0.04–2.00 μM with a lower limit of quantification of 0.04 μM. Coefficients of variation and absolute relative biases were <4.3% and 10.3%, respectively. The mean recovery for peptide was 91.6 ± 4.0%. Matrix effect study displayed ion suppression, and no carry-over and interferences were observed. There were no differences in CNA between healthy and TAC-treated patients. Furthermore, CNA showed maximum inhibition at 1 h after drug intake when TAC reached the highest blood concentration.
This method improves the extraction phase of PBMCs and achieves faster determination compared to other techniques, bringing us closer to be applied in daily laboratory practice.
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We describe the longitudinal follow-up of calcineurin activity and its clinical relevance in 4 de novo living-donor kidney transplant recipients treated with cyclosporine (n = 1) or tacrolimus (n = 3). The calcineurin activity in peripheral blood mononuclear cells was measured in combination with therapeutic drug monitoring during hospitalization. Serial blood samplings were performed after the oral administration of each drug to evaluate the temporal pharmacokinetic and pharmacodynamic profiles. Significant changes in enzyme activity were evaluated in relation to clinical outcomes. A nadir of calcineurin activity occurred at the maximum blood drug concentration within 4 h post-dose in most cases. Unlike cyclosporine, tacrolimus partially suppressed calcineurin activity throughout the dosing interval compared to the pre-dose level (cyclosporine, 62–67% inhibition; tacrolimus, 13–35% inhibition). Notably, calcineurin activity rapidly increased a few days before the onset of acute rejection in 2 patients, 1 receiving cyclosporine and 1 receiving tacrolimus, despite the achievement of therapeutic trough blood concentrations. These preliminary findings indicate that therapeutic monitoring of calcineurin activity in addition to the measurement of blood drug concentrations may be helpful to evaluate the pharmacodynamic effects of cyclosporine and tacrolimus early after renal transplantation.
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In contrast, polymorphisms of monocyte chemoattractant protein (MCP)-1 gene did not seem to show a relation to ARE among OLT recipients.66 Despite the progress in the understanding of the pharmacokinetics of the calcineurin inhibitors (CNI; CsA and TRL), in vitro pharmacodynamic assays of drug effect remain a difficult challenge.67 These 2 structurally related compounds inhibit mammalian target of rapamycin (mTORi), a critical intermediate in the transduction of signals triggering protein synthesis, proliferation and differentiation of T cells and a variety of other tissue cells.
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Pharmacologic tools to optimize therapyComparison of the Temporal Profile of Calcineurin Inhibition by Cyclosporine and Tacrolimus in Renal Transplant Patients

Abstract

Section snippets

Patients

Results

Discussion

Am J Transplant

Effect of immunosuppressive therapy on graft half-life projectionsThe Collaborative Transplant Study

Transplant Proc

CalcineurinStructure, function, and inhibition

Cell Biochem Biophys

Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A

Proc Natl Acad Sci USA

Identification of calcineurin as a key signalling enzyme in T- lymphocyte activation

Nature

Whole-blood calcineurin activity is not predicted by cyclosporine blood concentration in renal transplant recipients

Clin Chem

Pharmacologic tools to optimize therapy
Comparison of the Temporal Profile of Calcineurin Inhibition by Cyclosporine and Tacrolimus in Renal Transplant Patients