Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344628
Title: The pharmacokinetics of drugs in the ruminant animal
Author: Marriner, Susan E.
ISNI:       0000 0001 3619 2815
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1980
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Abstract:
The aim of this study was to investigate the effects of the rumen on the kinetics of drugs by measuring plasma and gastro-intestinal fluid concentrations of model drugs (weak acids and bases), after various routes of administration. The experimental animals used were Finn-Dorset sheep fitted with permanent ruminal, abomasal and duodenal cannulae, and the drugs chosen were meclofenarrate, an acidic drug, and levamisole, fenbendazole, oxfendazole and albendazole which are basic drugs. All of the drugs studied were absorbed to soma extent after oral administration. Levamisole only was absorbed from the rumen; absorption from this part of the gastro-intestinal tract was much slower than that from the more distal regions. For the other drugs studied, absorption from the rumen was negligible. Passive diffusion of drug from the systemic compartment into the rumen, either across the rumen wall or via the saliva, was found to occur with levamisole and meclofenamate, but not with the benzimidazole drugs or their metabolites, Levamisole administered subcutaneously, and benzimidazole metabolites formad in the systemic compartment were found to diffuse into abomasal fluid, reaching higher concentrations than those found in plasma at the same time. The kinetics of the benzimidazole drugs were found to be very slow, the drugs persisting in plasma and gastro-intestinal fluid for up to 9 days. This was attributed to the low water and lipid solubility of the drugs compared with that of levamisole and meclofenamate. Passage through the rumen, of the drugs studied, was found to slow the rate of absorption compared with that of drug administered directly into the abomasum. Oral administration of each of the drugs studied resulted, on almost every occasion, in scme of the drug being delivered directly to the abomasum by, the action of the reticular groove. The extent of ruminal by-pass was variable and usually small. It did not appear to be consistent for any individual animal. High concentrations of benzimidazole metabolites were found in plasma and in abomasal fluid after oral, intra-ruminal and intra-abomasal administration of the parent drug. The site of metabolism of the benzimidazoles was investigated in vitro. On incubation with hepatic microsomes both sulfide crugs, fenbendazole and albendazole, were oxidised to sulfoxides and sulfones. Reduction of fenbendazole sulfoxide (oxfendazole), and albendazole sulfoxide, also occurred during incubation in vitro with liver microsomes; both sulfoxides were found to undergo reduction to the sulfides on incubation with fresh ruminal fluid. No oxidation or reduction was found during incubation of sulfides or sulfoxides with abomasal fluid. The anthelmintic activities of albendazole and its two major metabolites, albendazole sulfoxide and albendazole sulfone were compared by administration of the compounds in feed to rats infected with Nippostrongylus braziliensis. Albendazole sulfoxide was found to have similar anthelmintic activity to albendazole, and albendazole sulfone was found to be non-active. The relevance of these findings to the suggested mode of action of these drugs is discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.344628  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry
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