title: Monitoring of tacrolimus concentrations in peripheral blood mononuclear cells: application to cardiac transplant recipients.
abstract: OBJECTIVE
  Despite the intensive therapeutic drug monitoring of tacrolimus (TAC) using trough whole blood concentrations, graft rejections occur in transplant recipient patients. Thus, other ways to monitor closely immunosuppressive treatments are necessary. A promising way of monitoring TAC treatments could be the measure of its concentrations inside of the lymphocyte cell. Whereas the pharmacokinetics of TAC in peripheral blood mononuclear cells (PBMCs) was evaluated in renal and liver transplant recipients, data regarding PBMC concentrations of TAC in cardiac transplant recipients are lacking. This study aimed, in cardiac transplant recipients: to validate a method for determination of TAC in PBMC, to investigate PBMC trough concentrations of TAC, and to evaluate their relationship with trough whole blood concentrations.
  
  
  METHODS
  We developed and validated a High-performance-liquid-chromatography tandem mass-spectrometry method of TAC quantitation in PBMC. The method was then evaluated by determining TAC concentrations in PBMC of 24 cardiac transplant recipients.
  
  
  RESULTS
  Twenty-four patients were prospectively included in the study. Tacrolimus PBMC concentrations displayed a large inter-individual pharmacokinetic variability (CV=71.4%) in the cohort. A lack of correlation between TAC whole blood trough concentrations and TAC trough concentrations in PBMCs was found (r=0.259; p=0.183).
  
  
  CONCLUSIONS
  Further studies should be implemented to evaluate the correlation between TAC concentrations in PBMC and clinical outcomes in cardiac transplant recipients to allow concluding whether monitoring TAC concentrations in PBMC is a good tool to prevent graft rejection in cardiac recipients.
authors: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 0203, Clinical Investigation Center, Rennes, France; EA4123, Barrières physiologiques et réponses thérapeutiques, Faculty of Pharmacy, Paris 11 University, Châtenay-Malabry, France. Electronic address: florian.lemaitre@chu-rennes.fr.
authors: Florian
authors: F
authors: Lemaitre
authors: Marie
authors: M
authors: Antignac
authors: Christine
authors: C
authors: Fernandez
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000737:chemistry; D016903:Drug Monitoring / Q000379:methods / Q000706:statistics & numerical data*; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: Cardiac transplant recipients; Heart transplantation; PBMC; Peripheral blood mononuclear cells; Pharmacokinetics; Tacrolimus; Transplantation