title: Conversion to Once-Daily Tacrolimus Results in Increased p38MAPK Phosphorylation in T Lymphocytes of Kidney Transplant Recipients.
abstract: BACKGROUND
  The once-daily formulation of tacrolimus (TAC(OD)) has been developed to overcome adherence problems. Conversion from the twice-daily TAC (TAC(BID)) formulation to TAC(OD) on a 1:1 basis, however, often leads to a decrease of TAC predose concentrations, which averages ∼15%. Switching between the two TAC formulations may thus influence drug efficacy and necessitates therapeutic drug monitoring. As an additional tool in transplantation diagnostics, phospho-specific flow cytometry was used to study the biological effects of conversion on p38MAPK phosphorylation, a kinase involved in T-lymphocyte activation.
  
  
  METHODS
  Stable renal transplant recipients (n = 12), at least 1 year after their transplantation, were converted from TAC(BID) to TAC(OD) on 1:1 mg for mg base. Comedication consisted of mycophenolate mofetil (n = 10) and prednisolone (n = 3). TAC whole-blood predose concentrations were determined by immunoassay before and 3 months after conversion. P38MAPK phosphorylation was measured in T lymphocytes by whole-blood phospho-specific flow cytometry.
  
  
  RESULTS
  Three months after conversion, no significant decreases in TAC predose concentrations (C0) were found (P = 0.54), whereas p38MAPK phosphorylation increased with 11.4% (P < 0.05) in CD4 and with 15.6% (P < 0.05) in CD8 T lymphocytes. The TAC C0 during treatment with TAC(BID) correlated inversely with p38MAPK phosphorylation in T lymphocytes (rs = -0.638; P < 0.05).
  
  
  CONCLUSIONS
  These results suggest that the measurement of p38MAPK phosphorylation status in T lymphocytes is a sensitive method to determine the biological effects of TAC before and after conversion from TAC(BID) to TAC(OD). This method could be a more sensitive tool for therapeutic drug monitoring of TAC.
authors.affiliation: *Department of Internal Medicine, Division of Nephrology and Transplantation; and †Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
authors.forename: Nynke M
authors.initials: NM
authors.lastname: Kannegieter
authors.forename: Nauras
authors.initials: N
authors.lastname: Shuker
authors.forename: Ramin
authors.initials: R
authors.lastname: Vafadari
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects*; D011239:Prednisolone / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood; D066027:Transplant Recipients; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D011239:Prednisolone; D048051:p38 Mitogen-Activated Protein Kinases; D009173:Mycophenolic Acid; D016559:Tacrolimus