Interspecies comparison of pharmacokinetics of the novel triazole antifungal agent SYN-2869 and its derivatives

The pharmacokinetics and distribution in tissue of several novel triazole a ntifungal agents were studied in different animal species in order to selec t an appropriate lead compound. The purpose of the study was also to determ ine species differences in pharmacokinetics for SYN azoles to select the mo st appropriate species for secondary efficacy and toxicological evaluation of the selected compound. SYN-2836, SYN-2869, SYN-2903, and SYN-2921 were r apidly absorbed into the systemic circulation and reached maximum concentra tions (C(max)s) of 7.31 +/- 2.53, 6.29 +/- 0.85, 6.16 +/- 0.39, and 3.41 +/ - 0.34 mu g/ml, respectively, in BALB/c mice after administration of an ora l 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 zer o to infinity (AUC(0-infinity)s) after administration of a single intraveno us dose of 20 mg/kg to mice varied between 25.0 and 63.6 mu g . h/ml. The h alf-life was in the range of 4.5 to 6 h. In Sprague-Dawley rats there was n o significant difference in AUG,, after administration of a single intraven ous dose of 20 mg/kg, but on oral administration, the bioavailability of SY N-2836 was extremely low, while that of SYN-2869 was only 14.7%. In New Zea land White rabbits the C-max and the time to reach C-max for SYN-2836 and S YN-2869 after administration of a single oral dose of 50 mg/kg were similar . There were significant differences in AUG,, and half-life between SYN-283 6 and SYN-2869. On the other hand, in beagle dogs the C-max and AUG(0-infin ity) of SYN-2836 after administration of a single oral dose of 30 mg/kg wer e 4.82 +/- 1.54 mu g/ml and 41.8 +/- 15.7 mu g . 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-2 869, SYN-2903, and SYN-2921 in mouse lungs were significantly different fro m each other. The ratios of the concentrations of the SYN atoles in lungs t o those in plasma were also significantly different from those for itracona zole. Among the SYN atoles the highest concentration in the lungs was found for SYN-2869. The higher level of distribution of SYN-2869 into lung tissu e was considered to contribute to the potent efficacy in respiratory tract infection models compared with the potency of itraconazole. Significant dif ferences in the pharmacokinetics of these compounds were observed in differ ent animal species, and selection of an animal model for further evaluation was based on results obtained from these studies.