Cyclosporine lymphocyte versus whole blood pharmacokinetic monitoring: correlation with histological findings

Barbari, A; Masri, Marwan; Stephan, A; Mokhbat, Jacques; Kilani, H; Rizk, S; Kamel, G; Joubran, Najat

doi:10.1016/s0041-1345(01)02190-x

Cited by 15 publications

(7 citation statements)

References 16 publications

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“…Depending on the level of P-gp activity, this could lead to either immunerelated or other nonrenal adverse events (for patients with low activity) or to increased risk of rejection (for patients with high activity). These observations are in agreement with our earlier report of cyclosporinetreated kidney transplant patients, [64][65][66] which was later confirmed by other investigators in cyclosporinetreated renal transplant recipients 63,67-69 and everolimus-treated cardiac transplant recipients, 70 on the weak association between whole blood levels of immunosuppressive drugs and their corresponding lymphocyte concentrations and on the stronger correlation of the latter with the rate of biopsy-proven acute rejection. Interestingly, no such associations have been yet described with mTOR inhibitors despite their similar effects to both CNIs on P-gp.…”

Section: Case Discussion and Review Of The Literaturesupporting

confidence: 93%

Untitled

2015

Exp Clin Transplant

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Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transitionmediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

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Section: Case Discussion and Review Of The Literaturesupporting

confidence: 93%

Untitled

2015

Exp Clin Transplant

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“…These observations suggest that despite whole blood levels in the therapeutic range, some subjects could have inadequate amounts of drug in the target cells. Barbari et al noticed lower cyclosporine PBMC trough or maximum levels in renal transplant patients with acute rejection compared to individuals without rejection, whereas no differences were observed in whole blood trough or maximum concentrations [32][33][34][35]. Our results also point to the fact that intraindividual PBMC and whole blood cyclosporine kinetic profiles were closely related.…”

Section: Cyclosporine Pharmacokinetics In Pbmcs and Whole Bloodsupporting

confidence: 70%

Influence of ABCB1 Gene Polymorphisms and P-Glycoprotein Activity on Cyclosporine Pharmacokinetics in Peripheral Blood Mononuclear Cells in Healthy Volunteers

Ansermot¹,

Rebsamen²,

Chabert³

et al. 2008

DML

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The calcineurin inhibitor cyclosporine is removed from lymphocytes by the drug efflux transporter P-glycoprotein (P-gp) encoded by the ABCB1 gene for which several single nucleotide polymorphisms (SNPs) have been identified. Of a total of 87 healthy volunteers genotyped for ABCB1 G2677T/A and C3435T SNPs, 10 GG-CC and 9 TT-TT individuals were selected and received a single oral dose of cyclosporine. Peripheral blood mononuclear cell (PBMC) ABCB1 mRNA expression, P-gp activity in CD4(+) and CD8(+) cells and the 24h cyclosporine pharmacokinetics in PBMCs and whole blood were determined. No correlation was observed between cyclosporine PBMC and whole blood levels (AUC(0-24), Spearman, r(S)=0.09, p=0.71). Intraindividual PBMC and whole blood levels followed parallel profiles that did not significantly differ with respect to t(max) (Wilcoxon, p=0.53) and t((1/2)) (p=0.49). Significant negative correlations between cyclosporine t((1/2)) in PBMCs and P-gp activity in CD4(+) (r(S)=-0.82, p=0.007) and CD8(+) (r(S)=-0.72, p=0.03) were observed among TT-TT subjects. Similarly, a negative correlation was detected in the GG-CC group between P-gp activity in CD4(+) and cyclosporine PBMC AUC(0-24) (r(S)=-0.69, p=0.03), as well as PBMC to whole blood AUC(0-24) ratio (r(S)=-0.60, p=0.07). Tested ABCB1 genotypes had no influence on cyclosporine pharmacokinetic parameters in PBMCs and whole blood. The haplotypes investigated were neither significantly correlated with PBMC ABCB1 mRNA expression nor with P-gp activity in CD4(+) and CD8(+). In conclusion, cyclosporine PBMC pharmacokinetics was influenced by P-gp activity and cyclosporine whole blood concentrations did not predict PBMC drug levels, suggesting that despite values in the therapeutic range, some subjects could have inadequate intracellular drug levels.

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“…Direct measurement of lymphocyte MPA concentrations may provide a better understanding of its immunosuppressive efficacy and distribution during graft rejection. The importance of such an approach has already been demonstrated for CsA [6][7][8][9] and TAC [10,11] by direct quantification of peripheral blood mononuclear cells (PBMCs), representing the target site of action. It has been suggested that lower PBMC CsA [9] and TAC [10] concentrations are associated with significantly higher incidences of graft rejection, which were not reflected by whole blood concentrations.…”

Section: Introductionmentioning

confidence: 99%