Pharmacokinetics and metabolism studies of antifilarial drugs derivatives of benzimidazole carbamate
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Date
1996
Authors
Ramanathan, Surash
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Abstract
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 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.
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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 compound
Description
Keywords
Metabolism studies , Benzimidazole carbamate