title: Unpredictable cyclosporin--fluconazole interaction in renal transplant recipients.
abstract: BACKGROUND
  Cyclosporin (CsA) is metabolized primarily in the liver by cytochrome P-450 enzymes. Concomitant use of fluconazole can increase CsA concentrations by inhibiting this enzyme system and the effect seems to be dose dependent, with no interaction noted when fluconazole is used in a dose of 100 mg/day. Two previous investigations studying this interaction while using higher doses of fluconazole have provided inconsistent results. Recommendations advising an empirical 50% CsA dosage reduction in these patients have not been tested in a prospective trial.
  
  
  METHODS
  We studied six renal transplant recipients on CsA immunosuppression in a prospective, unblinded, crossover trial. Baseline renal functions, CsA area under the curve (AUC), Cmax, Cmin, CsA clearance, and Tmax were compared with those 2, 4 and 7 days after starting fluconazole orally in a dose of 200 mg/day. From day 8 onwards, patients reduced CsA dose by 50% and the above parameters were repeated on day 14.
  
  
  RESULTS
  CsA AUC increased from 2887 +/- 1729 ng.h/ml on day 0 to 3842 +/- 1975 ng.h/ml on day 2 (P < 0.05), 4750 +/- 1718 ng.h/ml on day 4 (P< 0.01) and then decreased to 4052 +/- 1687 ng.h/ml on day 7 (P<0.01). Following CsA dose reduction by 50%, the mean AUC decreased significantly to 2330 +/- 1602 ng x h/ml (P<0.01). The Cmax showed a significant increase from 701 +/- 345 ng/ml on day 0 to 941 +/- 326 ng/ml (P < 0.01) on day 4 but decreased from 768 +/- 292 ng/ml on day 7 to 498 +/- 289 ng/ml on day 14, P<0.01. The mean Cmin increased from 207 +/- 138 ng/ml on day 0 to 274 +/- 168 ng/ml on day 4. No significant changes were observed in CsA clearance and Tmax. On repeated-measurement ANOVA, only the AUC and Cmax on day 4 of fluconazole were significantly higher than day 0 (P<0.001). There was a large interindividual variability in the degree of drug interaction between patients.
  
  
  CONCLUSIONS
  Fluconazole given orally in a dose of 200 mg/day is associated with significant increase in bioavailability of CsA. The maximum effect occurs on day 4 after starting fluconazole. Although repeated monitoring of CsA Cmin is convenient as opposed to repeated determination of AUC, changes in Cmin may not be sensitive enough to pick up this interaction. The increase in bioavailability of CsA is unpredictable in individual patients and all patients should be monitored with AUC near day 4 of treatment to guide CsA dosage reductions.
authors.affiliation: Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: K
authors.initials: K
authors.lastname: Sud
authors.forename: B
authors.initials: B
authors.lastname: Singh
authors.forename: V S
authors.initials: VS
authors.lastname: Krishna
authors.forename: K
authors.initials: K
authors.lastname: Thennarasu
authors.forename: H S
authors.initials: HS
authors.lastname: Kohli
authors.forename: V
authors.initials: V
authors.lastname: Jha
authors.forename: K L
authors.initials: KL
authors.lastname: Gupta
authors.forename: V
authors.initials: V
authors.lastname: Sakhuja
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D001682:Biological Availability; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D015725:Fluconazole; D003404:Creatinine