The pharmacokinetics of saccharin in rat and man
The pharmacokinetics of saccharin in rat and man
Saccharin has been shown to possess sex, organ and generation specificity in its carcinogenic effects during 2-generation feeding studies. The specificity light be related to differences in metabolism and/or tissue distribution of this non-nutritive sweetener. Metabolism studies using tic, reverse isotope dilution and reverse phase hplc failed to detect significant levels of metabolites in Sprague-Dawley rats given a wide range of saccharin doses (from a single oral dose of 60µg kg-1 to 5% saccharin diet ad libitum over 2-generations). The absence of detectable metabolism and the nucleuphilic nature of the saccharin molecule itself is important evidence that the tumours do not result from a classical electrophilic interaction with nucleophilic sites on informational macromolecules. The tissue levels of saccharin in rats given 5% saccharin diet over 2-generations did not reflect the specificity of the tumourigenic response, since the concentrations in the tissues of foetal rats were no higher than those observed in neonatal or adult animals, while the tissue levels in females given 5% saccharin diet for 22 days were higher than those found in corresponding male rats. The concentrations of saccharin in the plasma and tissues of male rats given 7.5 or 10% diet ad libitum were higher than predicted by linear extrapolation of the results from low dietary levels (0-3%). This observation prompted a comprehensive study of the pharmacokinetics in the rat which revealed that saccharin was absorbed slowly and incompletely from the gastrointestinal tract but eliminated rapidly in the urine. In male rats the plasma clearance process showed non-linear kinetics and was saturated by plasma levels in excess of 200-300µg ml''. The plasma concentrations in rats fed 7.5 or 10% saccharin diets were sufficient to cause reduced elimination which resulted in elevated tissue levels. A pharmacokinetic study in 3 human volunteers revealed that saccharin was incompletely absorbed from the gut but eliminated rapidly in the urine by similar processes to those observed in the rat. However, there was no evidence of reduced renal elimination over the plasma concentration range obtained (0.1-60µg ml-1). Thus, although the rat is a good pharmacokinetic model for man at low plasma saccharin levels, the extrapolation of results obtained with high doses is complicated by dose-dependent elimination and this must cast doubts over the extrapolation of results from cancer bioassays conducted at such levels.
University of Southampton
Sweatman, Trevor William
8f6862ba-9cbc-43c0-ac11-e79b148d7133
1981
Sweatman, Trevor William
8f6862ba-9cbc-43c0-ac11-e79b148d7133
Sweatman, Trevor William
(1981)
The pharmacokinetics of saccharin in rat and man.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Saccharin has been shown to possess sex, organ and generation specificity in its carcinogenic effects during 2-generation feeding studies. The specificity light be related to differences in metabolism and/or tissue distribution of this non-nutritive sweetener. Metabolism studies using tic, reverse isotope dilution and reverse phase hplc failed to detect significant levels of metabolites in Sprague-Dawley rats given a wide range of saccharin doses (from a single oral dose of 60µg kg-1 to 5% saccharin diet ad libitum over 2-generations). The absence of detectable metabolism and the nucleuphilic nature of the saccharin molecule itself is important evidence that the tumours do not result from a classical electrophilic interaction with nucleophilic sites on informational macromolecules. The tissue levels of saccharin in rats given 5% saccharin diet over 2-generations did not reflect the specificity of the tumourigenic response, since the concentrations in the tissues of foetal rats were no higher than those observed in neonatal or adult animals, while the tissue levels in females given 5% saccharin diet for 22 days were higher than those found in corresponding male rats. The concentrations of saccharin in the plasma and tissues of male rats given 7.5 or 10% diet ad libitum were higher than predicted by linear extrapolation of the results from low dietary levels (0-3%). This observation prompted a comprehensive study of the pharmacokinetics in the rat which revealed that saccharin was absorbed slowly and incompletely from the gastrointestinal tract but eliminated rapidly in the urine. In male rats the plasma clearance process showed non-linear kinetics and was saturated by plasma levels in excess of 200-300µg ml''. The plasma concentrations in rats fed 7.5 or 10% saccharin diets were sufficient to cause reduced elimination which resulted in elevated tissue levels. A pharmacokinetic study in 3 human volunteers revealed that saccharin was incompletely absorbed from the gut but eliminated rapidly in the urine by similar processes to those observed in the rat. However, there was no evidence of reduced renal elimination over the plasma concentration range obtained (0.1-60µg ml-1). Thus, although the rat is a good pharmacokinetic model for man at low plasma saccharin levels, the extrapolation of results obtained with high doses is complicated by dose-dependent elimination and this must cast doubts over the extrapolation of results from cancer bioassays conducted at such levels.
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Published date: 1981
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Local EPrints ID: 459141
URI: http://eprints.soton.ac.uk/id/eprint/459141
PURE UUID: 446868cf-75b1-47ae-a252-0a47601e9d8d
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Date deposited: 04 Jul 2022 17:05
Last modified: 23 Jul 2022 00:30
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Author:
Trevor William Sweatman
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