PHARMACOKINETICS AND METABOLISM STUDIES OF ANTIFILARIAL DRUGS DERIVATIVES OF BENZIMIDAZOLE CARBAMATE by SURASH RAMANATHAN

The pharmacokinetics and metabolism of two new antifilarial drugs, UMF-078 and UMF-058 have been investigated in suitable animal models with special emphasis on drug absorption and drug metabolism, the latter was to determine the possible metabolic products follO\ving metabolism in rats. Specific and sensitive high performance liquid chromatography techniques (HPLC) for UMF-078, UMF-058 and their respective putative metabolites has been developed. The availability of these HPLC techniques further facilitated investigation of the effects of dose regimens, formulation and routes on drug absorption in monkeys and dogs. In healthy monkeys, UMF-078 absorption was relatively better for UMF-078 salt than of UMF-078 base. With respect to dose escalation study of UMF-078 base a 3 1/2 fold increment in UMF078 absorption (AUC) was encountered when the dose was doubled from 100 to 200 mglkg. The effect of routes (i.m. vs. oral) on drug absorption in monkeys was also investigated Following i.m. administration UMF-078 absorption was observed to be poor and erratic when compared to oral administration of the same dosing schedule animals. . .. Studies were also initiated in dogs to investigate the effect of formulation and dose size on drug absorption. The overall absorption of UMF-078 is similar in group of animals receiving either UMF-078 salt or UMF-078 base .UMF-078 absorption was found to increase when the drug was given as divided dose (150 mglkg x 2; 50 mglkg x b.i.d. x 3) as compared to those administered with a single bolus dose of 300 mglkg of UMF078. In addition studies in dogs and monkeys also tend to suggest that FBZ and UMF060 were not the major metabolites ofUMF-078.