|Title:||Sorafenib biotransformation and the outcome of therapy in patients with advanced hepatocellular carcinoma|
|Publisher:||University of Sydney.|
Faculty of Pharmacy.
|Abstract:||Sorafenib (SRF) undergoes hepatic biotransformation and CYP3A4 is the main responsible enzyme for primary metabolism of SRF. The secondary metabolism of SRF was characterised in this study. Correlations existed with CYP3A activity whereas CYP3A5 only played a minor role. Taken together findings provide corroborating evidence for the role of CYP3A4 in the secondary metabolism of SRF. The reductive reaction of SRF N-oxide (M2) was characterised. CYP1A1 and CYP2B6 were the main responsible enzymes. The findings suggest a role for the reduction of the N-oxide metabolite in the biotransformation of SRF. SRF was shown to be an inhibitor of several CYP enzymes. M2 has stronger inhibitory effects than SRF on most CYPs. Given that M2 is present at plasma concentrations of 10% of SRF it might also contribute to the overall inhibition of CYPs and lead to increased toxicities. A non-randomised multicentre Phase II clinical study was designed. SRF was administered 400 mg orally, twice daily by a continuous dosing schedule. Blood samples were taken at each cycle of the study and Ctrough of SRF and its metabolites were quantified. The emergence of toxicities was assessed. There was a weak correlation between M5 trough concentrations and nausea. Correlations also existed with M5 trough concentrations and serum creatinine and total bilirubin. These findings suggest that liver and renal dysfunction might affect the pharmacokinetics of SRF, specifically with respect to M5 clearance. Directions for future study might include attempts to further characterise the extra-hepatic biotransformation pathways of SRF, determination of Phase II metabolism, investigating the effects of liver and renal dysfunction on the pharmacokinetics of SRF.|
|Access Level:||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions:||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work:||PhD Doctorate|
|Type of Publication:||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
|BASSIR GILLANI Tina - Final thesis.pdf||Thesis||9.18 MB||Adobe PDF|
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