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Title: Cyclosporine and drug metabolism
Author: Macintyre, Fiona
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1988
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Cyclosporine (CsA) (50mg/kg daily) for 0 - 14 days caused reductions in cytochrome p-450-dependent monooxygenase activities, phase II drug metabolising enzyme activities and non-drug metabolising enzyme activities in male Sprague-Dawley rats, which appeared to be self-limiting. The chronologies and extents of these reductions varied. Decreased monooxygenase activities were accompanied by decreased NADPH-cytochrome c-reductase activities. No isozyme-specific effect was evident and there was no direct correlation of drug metabolising activities with nephrotoxicity (which was progressive). The wide-ranging effects of CsA on membrane-bound drug and non-drug metabolising enzyme activities suggests an effect on membrane properties may be responsible. CsA did not decrease cytochrome P-450-dependent monooxygenase activities in female rats, nor was there any visual signs of CsA toxicity. A method for in vitro generation of CsA metabolites, a solvent extraction system and an HPLC system for separation of the metabolites was undertaken. The metabolite profiles produced on incubation of CsA with liver microsomes prepared from untreated and CsA-pretreated rats, rats pretreated with inducers of cytochrome P-450 (Phenobarbitone (PB), 3-methylcholanthrene (3-MC) and pregnenelone 16 -carbonitrile (PCN)) and human microsomes were compared. Michaelis-Menten kinetics for CsA disappearance were calculated. All microsome types metabolised CsA with the exception of CsA-pretreated rats. Biphasic kinetics were produced by orally dosed PB-induced microsomes, PCN-induced, control rat microsomes and human microsomes. Monophasic kinetics were obtained for a further orally dosed PB-induced microsome sample and PB (80mg/kg ip). CsA metabolism was induced 2.5 - 3.0 fold by PB and PCN microsomes compared with control rat microsomes. Human microsomes metabolised CsA faster than all rat microsomes. Metabolite 1 was the major metabolite produced by all microsome types. Only low levels of secondary and tertiary metabolites were produced by rat microsomes, even when sufficient levels of primary metabolites were present, suggesting that CsA and its metabolites may be metabolised by the same enzyme. Metabolites 17 and 18 were produced by all microsome types. Metabolites B and 21 were produced only by PB and PCN-induced rat microsomes and by human microsomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available