ABSTRACT
Recent researches on clinically used triazole antifungal reagents are focused on their pharmacokinetic disadvantage which increases the probability of inducing adverse effects in patients. For this point, in the present laboratory, Chemon Inc., has investigated new antifungal reactive compounds, KAF-200522 and its chloride form, KAF-200522 . HCl, which has a modified triazole structure. Pharmacokinetic data were measured with LC-MS/MS in male mice which were orally treated with the above compounds at 10 mg/kg. Tmax and t1/2 of KAF-200522 . HCl were comparable to KAF-200522, but AUC and Cmax were 1.4 and 1.6 times higher than those of KAF-200522, respectively. In beagle dogs, AUC and Cmax of KAF-200522 . HCl were 2.7 and 1.4 times higher than those of KAF-200522, and t1/2 was 3.5 times higher than that of KAF-200522. Moreover, in beagle dogs, the oral bioavailability value of KAF-200522 . HCl was revealed as 31.0% to contrast to 6.2% of KAF-200522. In 1-week repeated oral treatment toxicity study of KAF-200522 in male rats, inhibition of body weight gain was observed in 120 mg/kg treatment group, and loss of body weight was observed in 600 mg/kg treatment group. In the toxicokinetic study of KAF-200522, no accumulation after the systemic exposure was observed. In conclusion, as to the new antifungal drug development, KAF-200522 . HCl was considered to be advantageous in pharmacokinetic characteristics compared to KAF-200522.
Subject(s)
Animals , Dogs , Humans , Male , Mice , Rats , Area Under Curve , Biological Availability , Body Weight , Indicators and Reagents , Models, AnimalABSTRACT
KAF-200522 and its chloride form, KAF-200522-HCl, were invented in Chemon inc. as new triazole antifungal agents with excellent activities in vivo and in vitro against wide range of fungi. As a result of in vitro susceptibility measurements, 80% minimum inhibitory concentrations (MIC80) of both test articles against Candida albican sp. and Aspergillus fumigatus sp. were below 0.0156 microg/mL, which were over 4,100 times lower than those of fluconazole against fluconazole resistant C. albican sp. and A. fumigatus sp., and were over 16 times lower than those of amphotericin B against above same fungi. Additionally, against representative dermatophytes, Trichophyton sp., the MIC80s of both test articles were below 0.0156 microg/mL which were over 64 times lower than those of fluconazole and amphotericin B. As in vivo antifungal activities in A. fumigatus sp. infected mouse models, KAF-200522 treatment group at 600 mg/kg showed 80% survival rate which was 2 times higher than that of amphotericin B and showed 13.7 days in the mean survival time (MST) which was about 2.1 times higher than that of amphotericin B. But in KAF-200522-HCl treatment groups, all animals were found dead in contrast to 40% survival rate in amphotericin B treatment group, however dose dependent increases in MST was revealed. In conclusion, antifungal activities of KAF-200522 and its mimics, KAF-200522-HCl in vitro and in vivo were confirmed in this study, therefore the potentiality of the present compounds to be developed into new antifungal drug was expected.