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Title: Mimicking human drug metabolic reactions using microfluidic platforms
Author: Kulsharova, Gulsim K.
ISNI:       0000 0004 8500 3218
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Microfluidics has shown great potential in a range of biomedical and drug development applications. Investigating metabolic reactions in vitro via microfluidic devices presents a potential route to predict the toxicity levels of a tested compound in vivo. This project focuses on the development of a microfluidic platform integrated with a screen-printed electrode and immobilised with drug metabolism enzymes for this purpose. To develop a methodology for mimicry of metabolic enzyme reactions in microfluidics, a well-understood enzyme transketolase (TK) was used as a model enzyme. A simplified immobilisation for attaching the histidine-tagged TK was designed and applied to a poly(methyl methacrylate) (PMMA) surface. The technique showed successful enzyme retention and stability of the immobilisation layer in the PMMA device. A modular microfluidic chip for mimicry of phase I cytochrome P450 (P450) and phase II glucuronosyltransferase (UGT) enzyme-catalysed reactions was developed. A gold electrode immobilised with P450 was integrated into the chip for emulating metabolism of an antimalarial drug, artemether (AM). The P450 electrode allowed electrochemical generation of phase I metabolite, dihydroartemisinin (DHA) without the need for an expensive NADPH system conventionally used in batch. The product of the on-chip P450 reaction was coupled to the second microchannel with microparticles bearing UGT to mimic phase II glucuronidation reaction. The analysis showed a successful proof-of-concept of coupled AM metabolism on-chip producing a final metabolite, dihydroartemisinin-glucuronide (DHA-G). The microfluidic platform gives insight into individual enzymatic transformations of a model drug compound and presents an alternative to expensive in vitro methods.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available