title: Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors.
abstract: BACKGROUND
  Calcineurin inhibitors (CNI) and azole antifungal agents have been reported to interact in a disparate manner. The azole dose and route and the level of involvement of the liver and intestines have been implicated, although data are limited. A significant interaction may result in CNI toxicity, and withdrawal of the azole may result in subtherapeutic CNI concentrations. Fluconazole, available in both intravenous and oral formulations, is commonly used in transplant recipients and is ideal for determining the presence of a disparate effect on CNI concentrations. We retrospectively investigated the interaction of CNIs with fluconazole, evaluating CNI blood troughs corrected for daily CNI dose, the factors influencing the interaction, and the effect on clinical outcomes in renal and simultaneous pancreas kidney transplant recipients.
  
  
  METHODS
  Twenty-eight patients received a CNI and fluconazole during the calendar year 1999, but only 19 patients had documented CNI blood troughs and outpatient follow-up. There were 25 episodes of use in the 19 included patients. CNI blood troughs were evaluated for changes induced by fluconazole, given by both routes, and clinical outcomes were tracked.
  
  
  RESULTS
  Data demonstrated both intravenous and oral fluconazole alter CNI blood concentrations. Two metabolic patterns were observed, and we termed these convergent and divergent. Divergent metabolizers did not have significant interaction (n=5), and convergent metabolizers did have a significant interaction (n=15). One patient had a divergent episode after a previous convergent episode. The main contributors to the lack of interaction appeared to be female sex and African American ethnicity. Additionally, tacrolimus levels were significantly more affected than cyclosporine, during and after fluconazole administration. No patient experienced nephrotoxicity or cellular rejection related to antifungal therapy.
  
  
  CONCLUSIONS
  Oral and intravenous fluconazole appear to increase oral CNI trough concentrations to a similar extent even after adjusting for daily calcineurin dose. These interactions appear to be chiefly influenced by sex and ethnicity. Further prospective study is necessary to clarify this issue.
authors.affiliation: Department of Pharmacy Practice and Administration, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA. smathis@sbhcs.com
authors.forename: A S
authors.initials: AS
authors.lastname: Mathis
authors.forename: T
authors.initials: T
authors.lastname: DiRenzo
authors.forename: G S
authors.initials: GS
authors.lastname: Friedman
authors.forename: B
authors.initials: B
authors.lastname: Kaplan
authors.forename: R
authors.initials: R
authors.lastname: Adamson
mesh_terms: D000328:Adult; D001741:Black or African American; D000935:Antifungal Agents / Q000627:therapeutic use*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000627:therapeutic use; D004347:Drug Interactions; D005006:Ethnicity; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology / Q000706:statistics & numerical data*; D008297:Male; D016035:Pancreas Transplantation / Q000276:immunology / Q000706:statistics & numerical data*; D012189:Retrospective Studies; D012737:Sex Factors; D016559:Tacrolimus / Q000627:therapeutic use; D014481:United States
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D015725:Fluconazole; D016559:Tacrolimus