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Title: Drug interactions and metabolism of cyclosporin A and steroids by human liver microsomes in vitro
Author: Abu-Omar, Ghada M.
ISNI:       0000 0001 3392 5366
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1992
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1) The purpose of this work is to study the enzymology of cyclosporin A (CsA) metabolism by human liver in vitro , in particular investigating the basis for interindividual variations and drug interactions involving CsA metabolism, and to apply this knowledge to the development of a non-invasive test for predicting an individual's ability to metabolise CsA in vivo . The ultimate aim is to help to improve CsA therapy by understanding the factors which determine its metabolism in patients. 2) Human liver microsomes metabolised cyclosporin A (Km 25M) to eight identifiable metabolites, which were detected following incubation with [3H]-CsA in the presence of NADPH and aerobic O2. An interindividual variation in the generation of CsA metabolites was also observed. In addition, the formation rates of primary and secondary CsA metabolites were induced to different extents by 2 and 4 fold respectively, in liver microsomes prepared from patients treated with anticonvulsant treatment. Metabolite M1 formation was also induced by anticonvulsant treatment. 3) A significant correlation was observed between the total rate of CsA metabolism and cytochrome P-450IIIA concentration as measured by Western blot analysis, in 9 human liver microsomal preparations; 6 were obtained from untreated individuals and 3 from anticonvulsant-treated patients. This correlation was also present when the primary and the secondary metabolite profiles were considered separately. The kinetics of CsA metabolism by human liver microsomes demonstrated different Km and Vmax values for the formation rates of primary and secondary CsA metabolites. This suggests the possible involvement of two enzymes within the P-450IIIA family, responsible for the formation of primary and secondary metabolites, respectively. 4) Anti P-450IIIA antibodies inhibited the total rate of CsA metabolism in microsomal preparations from anticonvulsant-treated patients but to a lesser extent than those from untreated individuals. This suggests an involvement of other form(s) of P-450in CsA metabolism, responsible for between 20-30&'37 of CsA metabolic activity in human liver microsomes. However, these are unlikely to be P-450IIB1, P-450IA1 or P-450IIC, as none of the antibodies raised against these P450s significantly inhibited the metabolism of CsA. 5) From induction, inhibition and correlation studies, cytochrome P-450IIIA has been confirmed as being responsible for the major part of CsA metabolism in human and rat liver microsomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine