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Title: The effect of molecular modification on the kinetics of absorption, distribution, metabolism, and excretion of selected carbamates in rat
Author: Houston, James Brian
ISNI:       0000 0001 3582 389X
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1973
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The effect of molecular modification on the kinetics of absorption, distribution, metabolism and excretion of selected carbamates has been interpreted in terras of changes in physicochemical properties. The use of a series of aliphatic homologues of general structure R-O-CO-NH[2] was the basis for this work since these compounds show regular incremental changes in their apparent partition coefficients, aqueous solubilities, and ability to bind with macromolecules. Modification of the R group (eg branching of the aliphatic side chain or introduction of an aromatic group ) and N-methylation have also been studied as independant factors to elucidate the role of additional physico-chemical factors. The intestinal absorption of the homologous series was investigated using both in vitro and in situ techniques. An increase in absorption rate was observed when the chain length was increased from methyl to n-butyl. Further increase in the chain length resulted in a fall in the absorption rate. The absorption process appeared to be passive and no metabolism by the gut wall was detected. High tissue levels of carbamate were found using the in vitro system; especially with the more lipophilic carbamates. This phenomenon was not apparent using the in situ procedure. A similar lipophilicity parabola" was established with a series of N-methylated carbamates. These results have been discussed in terms of a two compartment model where both a hydrophilic barrier and a lipoidal membrane control the rate of intestinal absorption. The gastric absorption of the same two series of carbamates has been studied in situ. A good linear correlation betv/een the absorption rate constant and the partition coefficient over a range of 0.1 to 1000 was found. This has been contrasted with the absorption trends observed with the small intestine and it would appear that the role of the hydrophilic barrier is not as marked in controlling absorption rates from the stomach as it is in the intestine. Further comparison between the two organs have been made with respect to the role of steric factors and hydrogen bonding and to the effect of the non-ionic detergent Tween 80. The intestinal absorption behaviour of the weak acidic drug Carbenoxolone was also found to confirm to the "lipophilicity parabola". A pharmacokinetic profile of two carbamate insecticides---Carbaryl and Landrin---has been carried out. Despite their similar partitioning properties and absorption rates, these two compounds showed very different distribution and metabolism kinetics. Comparison of the half-lives of elimination of carbamate from plasma with half-lives of CO2 production showed that hydrolysis of the carbamate moiety proceeded through at least one intermediate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available