DISPOSITION OF AZOLE ANTIFUNGAL AGENTS .3. BINDING OF FLUCONAZOLE ANDOTHER AZOLES IN RAT-LIVER

It has been shown for the azole antifungal agents, ketoconazole and DT P, that hepatic binding, is a major determinant of their volume of dis tribution and this observation is of particular interest in view of th e well-documented avid binding of azoles to cytochromes P450. Whilst t he hepatic binding characteristics of these two compounds are similar, their hepatic clearance differs markedly in terms of the rate of meta bolism and the number and nature of metabolites produced. Fluconazole is a bis-triazole drug similar in structure to DTP but not subject to metabolism in rat. We have demonstrated by means of steady-state infus ion studies the clearance of this azole (1.85ml/min/kg) to be independ ent of blood concentration over a 0.01-50mg/L range. Also fluconazole plasma protein binding is minimal (9.5%) and its blood:plasma ratio un ity over a similar concentration range. Liver:blood partition coeffici ents for fluconazole are concentration dependent ranging from 30 to 2. The volume of distribution term is also nonlinear with concentration and can be correlated with the liver:blood partition coefficient. Thes e findings are discussed together with earlier documented data on keto conazole and DTP in terms of a tissue binding role for hepatic cytochr omes P450. The similarity in behaviour of the hepatic partitioning of the three azoles contrasts markedly with the nature of (or lack of) he patic metabolism.