title: Salivary concentrations of ketoconazole and fluconazole: implications for drug efficacy in oropharyngeal and esophageal candidiasis.
abstract: OBJECTIVE
  To determine whether salivary concentrations of ketoconazole and fluconazole may explain the apparent disparity between in vitro activity and clinical efficacy observed with these drugs.
  
  
  METHODS
  Healthy subjects received a single oral dose of ketoconazole 400 mg or fluconazole 100 mg in a randomized, crossover fashion. Saliva was collected at 0, 1, 2, 3, 6, 12, and 24 hours. Blood samples were obtained at 2 and 24 hours. Salivary concentrations and plasma concentrations for each drug were determined by HPLC. Minimum inhibitory concentration (MIC) testing was determined in triplicate on 6 clinical isolates of Candida albicans, and times over the median MIC values were calculated.
  
  
  METHODS
  Eight subjects completed the study.
  
  
  RESULTS
  The mean (+/- SD) peak salivary concentration for ketoconazole was 0.119 +/- 0.050 microgram/mL at 3 hours; no subject had a detectable ketoconazole salivary concentration at 24 hours. At 2 and 24 hours, mean ketoconazole plasma concentrations were 7.64 +/- 3.87 and 0.11 +/- 0.05 microgram/mL, respectively. The saliva to plasma concentration ratio at 2 hours was 0.01. The mean peak salivary concentration of fluconazole was 2.56 +/- 0.34 microgram/mL at 3 hours. At 24 hours, the mean salivary concentration was 1.44 +/- 0.33 microgram/mL. At 2 and 24 hours, mean fluconazole plasma concentrations were 4.39 +/- 3.33 and 3.72 +/- 2.83 micrograms/mL, respectively. The saliva to plasma concentration ratio at 2 hours was 0.55. Median MIC values were 0.0625 microgram/mL (range 0.0313-0.125) for ketoconazole and 0.25 microgram/mL (range 0.125-0.5) for fluconazole. Calculated times over which ketoconazole and fluconazole exceeded the median MICs in saliva were approximately 13 and greater than 24 hours, respectively.
  
  
  CONCLUSIONS
  After a single oral dose, fluconazole achieved higher salivary concentrations than did ketoconazole. This may explain the increased clinical efficacy of fluconazole in the treatment of oropharyngeal-esophageal candidiasis when compared with ketoconazole.
authors.affiliation: College of Pharmacy, Ohio State University, Columbus 43210.
authors.forename: R W
authors.initials: RW
authors.lastname: Force
authors.forename: M C
authors.initials: MC
authors.lastname: Nahata
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004935:Esophageal Diseases / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D015725:Fluconazole / Q000032:analysis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000032:analysis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008826:Microbial Sensitivity Tests; D009960:Oropharynx; D010608:Pharyngeal Diseases / Q000188:drug therapy* / Q000378:metabolism; D012463:Saliva / Q000737:chemistry*
chemical_list: D015725:Fluconazole; D007654:Ketoconazole