Cm. Ervine et Jb. Houston, DISPOSITION OF AZOLE ANTIFUNGAL AGENTS .3. BINDING OF FLUCONAZOLE ANDOTHER AZOLES IN RAT-LIVER, Pharmaceutical research, 11(7), 1994, pp. 961-965
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.