title: Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.
abstract: BACKGROUND
  Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation.
  
  
  METHODS
  We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment.
  
  
  RESULTS
  The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level.
  
  
  CONCLUSIONS
  We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.
authors.affiliation: Service de Néphrologie et de Transplantation Rénale, Hôpital Saint Louis, Paris, France. dany.anglicheau@biomedicale.univ-paris5.fr
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
authors.forename: Marie Hélène
authors.initials: MH
authors.lastname: Schlageter
authors.forename: Frank
authors.initials: F
authors.lastname: Martinez
authors.forename: Bruno
authors.initials: B
authors.lastname: Cassinat
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
mesh_terms: D000328:Adult; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D008775:Methylprednisolone