SYSTEMIC ANTIFUNGAL AZOLES PHARMACOLOGY

The fungistatic activity of azole compounds and the fungicidal activit y of amphotericin B have to be interpretated in the light of the resul ts of pharmacodynamic studies, especially by taking into account the r ole of polymorphonuclear celles and the post-antifungal effect. The la tter is sometimes long lasting but its clinical relevance remains to b e precised, From a pharmacokinetic (PK) point of view, oral bioavailab ility of fluconazole (Flu) is neither affected by an increased gastric pH (resulting from antiacid treatments, AIDS,...), nor by the time of drug intake or food. Conversly, itraconazole (Itr) and ketoconazole ( Ket) bioavailability is dramatically decreased (by more than 50 %) by achlerhydria, and both have to be taken with food to increase their ab sorption. Ket and Itr are extensively metabolised and their kinetics i s saturable (dose-dependent and time-dependent). The metabolic clearan ce of these two compounds accounts for 90 % of their elimination clear ance. Among the 30 metabolites of Itr, only hydroxyitraconazole (OH-It r) is fungistatic (with an activity similar to that of Itr). Systemic concentrations of OH-Itr are 1,5 to 2 times higher than those of Itr. Conversly, Flu is weakly metabolised(10 to 25 %), its kinetics are lin ear and its elimination proceeds mainly by renal route. Elimination ha lf-lives of Flu, Itr, OH-Itr and Ket are respectively 20-40h, 60-72h, 20-25h and 5-10h. A loading dose is therefore recommanded for Flu and Itr, Tissular concentrations of Flu and Itr are most often higher than those in plasma (respectively 1 to 3 times and 2 to 5 times), Among t he diseases wich are able to modify the kinetics of azole compounds an d require a dosing adjustement, the most important are: neutropenia, w hich reduces bioavailability of Ket and Itr, hepatic insufficiency, wh ich reduces the elimination rate of Ket and Itr, severe renal failure, which results in a 2 to 3 times increase of Flu half-life, continuous ambulatory peritoneal dialysis, which induces a 4 times longer Flu ha lf-life and a 4 times lower bioavailability of Itr. Concerning drug in teractions, enzymes inducers (rifampicine, phenytoin, phenobarbital) a ffect widely azoles kinetics, especially those of Itr and Ket, Convers ly, azoles antifungals are enzyme inhibitors which affect the kinetics of coadministred drugs such as terfenadine, ciclosporin and benzodiaz epines.