title: Chronopharmacokinetics of mycophenolic acid and its glucuronide and acyl glucuronide metabolites in kidney transplant recipients converted from cyclosporine to everolimus.
abstract: BACKGROUND
  The influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied.
  
  
  METHODS
  We evaluated daytime and nighttime steady-state MPA, MPAG, and acyl-MPAG pharmacokinetics in 24 stable kidney transplant recipients while receiving cyclosporine and 28 days after conversion from CsA to EVR. The effect of concomitant treatment and the circadian difference on AUC(t,ss) and C(max,ss) were assessed using a linear mixed model.
  
  
  RESULTS
  After conversion from CsA to EVR, MPA AUC(t,ss) was 43% higher (29% daytime and 58% during nighttime), whereas MPAG AUC(t,ss) was 33% lower (35% daytime and 30% during nighttime) and acyl-MPAG AUC(t,ss) was 31% lower (36% during daytime and 26% nighttime). Compared with daytime, MPA AUC(t,ss) was 25% lower (32% with CsA and 17% with EVR), MPAG AUC(t,ss) was 24% lower (26% with CsA and 21% with EVR), and acyl-MPAG AUC(t,ss) was 26% lower (32% with CsA and 21% with EVR) during nighttime. After conversion from CsA to EVR, MPAG:MPA and acyl-MPAG:MPA AUC(t,ss) ratios were 50% lower but were not different during daytime compared with nighttime EC-MPS administration. There was no correlation between CsA or EVR concentrations with MPA, MPAG, and acyl-MPAG exposures during daytime and nighttime. At least 1 adverse event was reported in 70.8% of patients receiving EC-MPS and CsA and in 91.7% receiving EC-MPS and EVR.
  
  
  CONCLUSIONS
  In stable kidney transplant recipients receiving EC-MPS and steroids, exposures to MPA, MPAG, and acyl-MPAG were lower during nighttime compared with daytime, both with CsA or EVR. This circadian effect on MPA exposure did not correlate with CsA or EVR concentrations or with altered MPAG and acyl-MPAG formation.
authors.affiliation: Nephrology Division, Hospital do Rim e Hipertensão, Universidade Federal de São Paulo, São Paulo, Brazil. heliotedesco@hrim.com.br
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco-Silva
authors.forename: Claudia Rosso
authors.initials: CR
authors.lastname: Felipe
authors.forename: Alan
authors.initials: A
authors.lastname: Slade
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schmouder
authors.forename: Jose Osmar
authors.initials: JO
authors.lastname: Medina Pestana
mesh_terms: D000305:Adrenal Cortex Hormones / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D001711:Biotransformation / Q000187:drug effects; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000009:adverse effects; D000068338:Everolimus; D005260:Female; D020719:Glucuronides / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D011355:Prodrugs / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D013608:Tablets, Enteric-Coated
chemical_list: D000305:Adrenal Cortex Hormones; D020719:Glucuronides; D007166:Immunosuppressive Agents; D011355:Prodrugs; D013608:Tablets, Enteric-Coated; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus