title: Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients.
abstract: BACKGROUND
  We investigated cyclosporine A (CsA) concentrations at the site of action, inside T-lymphocytes, to evaluate its applicability as a new supplementary therapeutic drug monitoring method after renal transplantation.
  
  
  METHODS
  In this prospective single-center study, 20 kidney transplant recipients, mean age 54 (range 21-74) years, on CsA-based immunosuppression were included within 2 weeks posttransplant and followed for 3 months. Nine patients also had one full 12-hour pharmacokinetic profile performed. T-lymphocytes were isolated from 7 ml whole blood using Prepacyte and intracellular CsA concentrations were determined using a validated liquid chromatography double mass spectrometry method.
  
  
  RESULTS
  Seven patients (35%) experienced acute rejections (all biopsy verified) during the first three months posttransplantation. Intracellular CsA concentrations tended to decline 1 week prior to acute rejection and the decrease was significant (-27.1+/-14.6%, P=0.014) three days before the rejection episodes were recognized clinically. In addition, the intracellular CsA area under the curve 0-12 measured during stable phase was 182% higher in the rejection-free patients (P=0.004). There was no difference between patients experiencing rejection and the rejection-free patients with respect to CsA C2-levels, dose (mg/kg), human leukocyte antigen mismatch, donor age, recipient age, or ABCB1 genotyping.
  
  
  CONCLUSIONS
  Intracellular CsA T-lymphocyte concentrations declined significantly 3 days prior to a rejection episode and there was a general lower intracellular exposure of CsA in recipients experiencing rejection. Intracellular measurement of CsA therefore seems to have a potential to further improve individualization of therapeutic drug monitoring. Larger studies are needed to elucidate the role for intracellular T-lymphocyte measurements in ordinary clinical care, for both CsA and other immunosuppressive drugs.
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. pal.falck@farmasi.uio.no
authors.forename: Pål
authors.initials: P
authors.lastname: Falck
authors.forename: Anders
authors.initials: A
authors.lastname: Asberg
authors.forename: Heidi
authors.initials: H
authors.lastname: Guldseth
authors.forename: Sara
authors.initials: S
authors.lastname: Bremer
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Akhlaghi
authors.forename: Jan L E
authors.initials: JL
authors.lastname: Reubsaet
authors.forename: Per
authors.initials: P
authors.lastname: Pfeffer
authors.forename: Anders
authors.initials: A
authors.lastname: Hartmann
authors.forename: Karsten
authors.initials: K
authors.lastname: Midtvedt
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine