Pharmacokinetics and metabolism studies of antifilarial drugs derivatives of benzimidazole carbamate

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dc.contributor.authorRamanathan, Surash
dc.date.accessioned2015-07-30T03:41:24Z
dc.date.available2015-07-30T03:41:24Z
dc.date.issued1996
dc.description.abstractThe 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 UMF- 078 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 UMF- 078. In addition studies in dogs and monkeys also tend to suggest that FBZ and UMF- 060 were not the major metabolites ofUMF-078. The pharmacokinetics and efficacy of UMF-058 in monkeys infected with Brugia malayi were also investigated. The overall UMF-058 oral absorption (AUCo-t) was similar for both single (250 mg/kg) and multiple dose regimen (50 mg/kg x 5). Neither single nor multiple oral dose regimens demonstrated adultcidal activity against B. malayi in infected monkeys. However, multiple dose regimen of UMF-058 was microfilaricidal against B. malayi. The metabolism of UMF-078 was investigated in rats. UMF-078 and its metabolites FBZ and UMF-060 all undergo carbamate hydrolysis. The importance ofthese metabolites were found in the order ofD-UMF-078 < D-UMF- 060 < FBZ < UMF-060 < D-FBZ. A comparative metabolism study of UMF-078 and FBZ in rats were also initiated. D-UMF-060, UMF-060 and D-FBZ were encountered in blood of rats having received UMF-078 but not in animals treated with FBZ. This tend to suggest that these metabolites probably derived from other alternative pathway of UMF-078 rather than via FBZ. The pre-clinical information described has improved our understanding of UMF-078 and thus provides the basis for further evaluation of this new candidate antifilarial compounden_US
dc.identifier.urihttp://hdl.handle.net/123456789/966
dc.language.isoenen_US
dc.subjectMetabolism studiesen_US
dc.subjectBenzimidazole carbamateen_US
dc.titlePharmacokinetics and metabolism studies of antifilarial drugs derivatives of benzimidazole carbamateen_US
dc.typeThesisen_US
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