Salivary concentrations of ketoconazole and fluconazole: implications for drug efficacy in oropharyngeal and esophageal candidiasis.
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.
Force
R W
RW
College of Pharmacy, Ohio State University, Columbus 43210.
Nahata
M C
MC
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*
D015725:Fluconazole; D007654:Ketoconazole