The pharmacokinetics and distribution in tissue of several novel
triazole antifungal agents were studied in different animal species in order to select an appropriate lead compound. The purpose of the study was also to determine species differences in pharmacokinetics for SYN
azoles to select the most appropriate species for secondary efficacy and toxicological evaluation of the selected compound.
SYN-2836,
SYN-2869, SYN-2903, and SYN-2921 were rapidly absorbed into the systemic circulation and reached maximum concentrations (C(max)s) of 7.31 +/- 2.53, 6.29 +/- 0.85, 6.16 +/- 0.39, and 3.41 +/- 0.34 microg/ml, respectively, in BALB/c mice after administration of an oral dose of 50 mg/kg of
body weight, with bioavailability being greater than 45% in all mice. The areas under the concentration-time curve from time zero to infinity (AUC(0-infinity)s) after administration of a single intravenous dose of 20 mg/kg to mice varied between 25.0 and 63.6 microg. h/ml. The half-life was in the range of 4.5 to 6 h. In Sprague-Dawley rats there was no significant difference in AUC(0-infinity) after administration of a single intravenous dose of 20 mg/kg, but on
oral administration, the bioavailability of
SYN-2836 was extremely low, while that of
SYN-2869 was only 14.7%. In New Zealand White rabbits the C(max) and the time to reach C(max) for
SYN-2836 and
SYN-2869 after administration of a single oral dose of 50 mg/kg were similar. There were significant differences in AUC(0-infinity) and half-life between
SYN-2836 and
SYN-2869. On the other hand, in beagle dogs the C(max) and AUC(0-infinity) of
SYN-2836 after administration of a single oral dose of 30 mg/kg were 4.82 +/- 1.54 microg/ml and 41.8 +/- 15.7 microg. h/ml, respectively, which were threefold higher than those of
SYN-2869. The concentrations of the SYN compounds in tissue indicated that the AUC(0-infinity)s of
SYN-2836,
SYN-2869, SYN-2903, and SYN-2921 in mouse lungs were significantly different from each other. The ratios of the concentrations of the SYN
azoles in lungs to those in plasma were also significantly different from those for
itraconazole. Among the SYN
azoles the highest concentration in the lungs was found for
SYN-2869. The higher level of distribution of
SYN-2869 into lung tissue was considered to contribute to the potent efficacy in
respiratory tract infection models compared with the potency of
itraconazole. Significant differences in the pharmacokinetics of these compounds were observed in different animal species, and selection of an animal model for further evaluation was based on results obtained from these studies.