DISPOSITION OF AZOLE ANTIFUNGAL AGENTS .2. HEPATIC BINDING AND CLEARANCE OF DICHLOROPHENYL-BIS-TRIAZOLYLPROPANOL (DTP) IN THE RAT

DTP (dichlorophenyl-bis-triazolylpropanol) was evaluated as a probe of drug-cytochromes P450 interactions in vitro and in vivo. Studies with rat liver microsomes demonstrate that DTP shows similar P450 binding affinity to its analog, ketoconazole, as determined by P450 difference spectra and inhibition of the metabolism of methoxycoumarin. As a mor e polar azole, DTP shows less affinity for rat plasma albumin (fractio n unbound 0.56) than ketoconazole (fraction unbound 0.037). DTP metabo lism is simpler than that of ketoconazole, with only one pathway, N-de alkylation which removes a triazole ring to yield DTP glycol. This pri mary metabolite is further metabolised to a carboxylic acid, a glycol glucuronide and a third unknown secondary metabolite (probably an acid glucuronide). Over a dose range of 0.1-24mg/kg there is complete mass balance recovery in urine via the five metabolites and unchanged drug . However DTP metabolism is dose dependent and while the affinity of D TP for the cytochromes P450 carrying out the initial dealkylation is h igh (1.5 mu M based on unbound blood concentration), the capacity of t he reaction is low (1nmole/min). Under linear conditions, metabolic cl earance is low (19ml/h), but ten-fold higher than renal clearance. The liver is the major distribution site for both DTP and ketoconazole. A t low DTP concentrations, a specific high affinity process dominates t he hepatic binding of DTP resulting in a liver:blood partition coeffic ient of approximately 30. Hepatic binding is concentration dependent a nd the progressive decrease in partition coefficient observed as the d ose of DTP is escalated is coincident with a decrease in volume of dis tribution. The two saturable processes involved in the disposition of DTP result in an unusual concentration dependency in the blood concent ration-time profile of this azole. Following administration of a high dose (10mg/kg) of DTP the log concentration-time profile is sigmoidal. At high concentrations (above 1mg/L) both the N-dealkylation and the hepatic binding of DTP are saturated, but as concentrations fall to ap proximately 0.05mg/L the former process becomes linear and the time pr ofile is convex over this concentration range. At later times as DTP c oncentrations decline further, the tissue binding also reaches the lin ear region and the time profile becomes concave. Only at low concentra tions (below 0.05mg/L) do both processes become first order and the tr ue half life is evident.