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Mimicking Human Drug Metabolic Reactions using Microfluidic Platforms

Kulsharova, Gulsim K; (2019) Mimicking Human Drug Metabolic Reactions using Microfluidic Platforms. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Mimicking Human Drug Metabolic Reactions using Microfluidic Platforms
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
URI: https://discovery.ucl.ac.uk/id/eprint/10080687
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