Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.796081
Title: The determination and pharmacokinetics of methimazole in biological fluids
Author: Donnelly, Mary Clare
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1988
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Abstract:
The Determination and Pharmacokinetics of Methimazole in Biological Fluids. The development of methimazole therapy, its mechanism of action and pharmacokinetics in man have been briefly reviewed. Specific, sensitive analytical methods were developed for methimazole and 3-methyl-2-thiohydantoin using gas chromatography- mass spectrometry. Trideutromethylimidazole was successfully synthesised and used as the internal standard. Extraction methods were developed for the separation of methimazole from various biological media. Using these specific methods, various clinical investigations were undertaken. Dosage linearity was shown when the plasma concentrations and kinetics of patients on a low dosage regimen where compared to those on a high dosage regimen. A lack of accumulation was also indicated as the plasma concentrations were shown to be at steady-state. Plasma concentrations of methimazole could be correlated with its effect on the inhibition of organification. Thus, the great divergence in the therapeutic response to the drug in thyrotoxicosis is obviously not due to differences in plasma pharmacokinetics or the extent of inhibition of organification of iodine. No significant differences between pharmacokinetic parameters after oral administration to euthyroid and hyperthyroid patients were observed. Thus, it appears that thyroid hormones do not depress or increase the metabolism of methimazole and therefore there are no pharmacokinetic reasons to adjust the dose of methimazole during treatment of thyrotoxicosis. Results for intrathyroidal concentrations supported the concept that methimazole is actively concentrated in the thyroid gland by showing no linearity with dose, an increase in thyroid/plasma concentration ratios with time and a decrease in thyroid/plasma concentration ratio with increasing dose thus indicating a saturated system. However, results for the percentage inhibition of iodide organification appears to be in direct conflict with the intrathyroidal levels. It is likely that the perchlorate discharge test underestimates the duration of action of methimazole as it does not gauge the extent of inhibition of coupling by methimazole. The analysis of infant plasma samples in conjunction with maternal plasma and milk samples showed that the maternal milk/plasma concentration ratio approached unity and that infant plasma levels of methimazole were significant. However, the clinical indices showed no abnormalities in their thyroid function. Therefore, with low doses and careful thyroid monitoring, methimazole is suitable for the treatment of hyperthyroidism in breast-feeding mothers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796081  DOI: Not available
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