Fluconazole and other azoles: translation of in vitro activity to in vivo and clinical efficacy.
Fluconazole is polar, soluble in water, and metabolically stable and exhibits low protein binding. In contrast, other systemic azoles are lipophilic, metabolically vulnerable compounds with high protein binding and negligible solubility in water. The physical and pharmacokinetic properties of these drugs plus their inherent antifungal potency determine their efficacy. Although fluconazole is less active than ketoconazole in vitro, its distribution throughout the body and the high levels of free drug reached in the blood contribute to and are of value in predicting its efficacy. Even for ketoconazole the levels of free drug in blood may be indicative of efficacy. For very lipophilic agents (itraconazole), blood levels of drug are very low, and organ levels may correlate better with efficacy, although tissue binding will be high and total drug levels in an organ may be misleading indicators of efficacy. The excellent efficacy of fluconazole in vivo despite its low activity in vitro has caused confusion. Consequently, a disk test is being developed to assess whether fungal isolates are sensitive to therapeutically achievable levels of drug.
Research Department, Pfizer Limited, Sandwich, Kent, United Kingdom.
P F
PF
Troke
R J
RJ
Andrews
G W
GW
Pye
K
K
Richardson
D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001393:Azoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005658:Fungi / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009181:Mycoses / Q000188:drug therapy*; D014018:Tissue Distribution
D000935:Antifungal Agents; D001393:Azoles; D015725:Fluconazole