Hl. Bomont et al., DISPOSITION OF AZOLE ANTIFUNGAL AGENTS .2. HEPATIC BINDING AND CLEARANCE OF DICHLOROPHENYL-BIS-TRIAZOLYLPROPANOL (DTP) IN THE RAT, Pharmaceutical research, 11(7), 1994, pp. 951-960
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.