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Title: The role of lipophilicity in the kinetics of absorption, distribution, metabolism and excretion of selected carbamates in the rat
Author: Wood, Stuart Gordon
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1977
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The role of lipophilicity in governing the kinetics of absorption, distribution, metabolism and excretion of selected aliphatic carbamates has been investigated. The use of a series of aliphatic carbamate homologues of general structure R-O-CO-NH[2] was the basis of these studies since these compounds show regular incremental changes in, and cover a wide range of, apparent partition coefficient. The carbamate homologues are also stable and unionised in aqueous solution and can thus be considered as a single entity in kinetic studies. Studies on the interaction of the carbamates with a phosphatidylcholine model membrane system (liposomes) showed that increasing carbamate chain length produced increasing destabilisation of the liposome membranes. It was found that the destabilisation was associated with incorporation of the carbamates into the lipid membrane. Four radiolabelled carbamates were used to investigate further the previously demonstrated parabolic relationship between intestinal absorption rate and partition coefficient. The in situ small Intestine preparation of either fed or 18 hour starved rats showed that the "lipophilicity parabola" was still operative using very low carbamate concentrations. The colonic absorption of the carbamate series has been studied in situ. The absorption process appeared to be passive and no metabolism by the colon membrane was detected. A linear correlation between the absorption rate constant and partition coefficient was found. The marked difference between the absorption profiles obtained for the colon and small intestine indicate that the absorptive process is much simpler in the colon. Concurrent water flux was found to have no effect on the absorption of the homologues from the colon. The pharmacokinetic disposition and overall metabolic fate of four radiolabelled carbamates have been investigated. Consideration of the proportions of dose excreted in the expired air and in the urine indicated that carbamate metabolism took place by two competing pathways. A hydrolytic route of metabolism appeared to be favoured by the shorter chain carbamates whereas various metabolic transformations on the intact carbamate molecule took place extensively for the longer chain carbamates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available