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Title: Analytical studies on the N-dealkylation of drug molecules by Cunninghamella sp.
Author: Gibson, Mark
ISNI:       0000 0001 3497 7125
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 1984
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In the Introduction the importance of N-dealkylation in pharmaceutical studies is summarised and the scope and potential advantages of microbial transformations in effecting N-dealkylation are examined. Possible applications of chromatographic and spectroscopic techniques to the study of microbial transformations are discussed. Chapter 2 describes the development of quantitative HPLC techniques for the determination of a model substrate codeine, and its N-demethylated transformation product, norcodeine, from microbial transformation mixtures. Extraction procedures applicable to 7 litre fermenter cultures are also investigated. The effect of carbon source and substrate concentration on the growth and N-demethylation of codeine by Cunninghamella sp. are investigated in Chapter 3. Chapter 4 describes the development of procedures for the preparation of a cell-free extract from Cunninghamella sp. with optimal N-demethylase activity. Reaction conditions for N- demethylation of codeine by cell-free extracts of C. bainieri are optimised in terms of substrate concentration and co-factor requirements. Kinetic data for the N-demethylation of codeine and codeine N-oxide by C. bainieri are presented in Chapter 5. The effect of selected inducers and specific enzyme inhibitors is also examined. A reaction mechanism for the N-demethylation of codeine by cell-free extracts of C. bainieri is proposed. Chapter 6 describes the development and application of a 13C NMR spectroscopic technique to detect the possible intermediates in the N-demethylation of codeine by cell-free extracts of C. bainieri, and provides further evidence in support of the proposed reaction mechanism. In Chapter 7 a HPLC technique is employed to estimate the lipid solubility of a selected series of 1,4-benzodiazepines from retention data. The dependence on substrate lipophilicity, of N-dealkylation of these compounds by C. bainieri, is examined. The data are considered with reference to current microbial transformation literature. The proposed mechanism of microbial N-demethylation is compared to mammalian transformations of similar substrates and suggestions for future study are emphasised.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry