Drug glucuronidation assays on human liver microsomes immobilized on microfluidic flow-through reactors

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http://hdl.handle.net/10138/325598

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Kiiski , I , Ollikainen , E , Artes , S , Järvinen , P , Jokinen , V & Sikanen , T 2021 , ' Drug glucuronidation assays on human liver microsomes immobilized on microfluidic flow-through reactors ' , European Journal of Pharmaceutical Sciences , vol. 158 , 105677 . https://doi.org/10.1016/j.ejps.2020.105677

Title: Drug glucuronidation assays on human liver microsomes immobilized on microfluidic flow-through reactors
Author: Kiiski, Iiro; Ollikainen, Elisa; Artes, Sanna; Järvinen, Päivi; Jokinen, Ville; Sikanen, Tiina
Contributor: University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Tiina Sikanen / Chemical Microsystems Lab
University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Tiina Sikanen / Chemical Microsystems Lab
University of Helsinki, Drug Research Program
Date: 2021-03-01
Language: eng
Number of pages: 9
Belongs to series: European Journal of Pharmaceutical Sciences
ISSN: 0928-0987
URI: http://hdl.handle.net/10138/325598
Abstract: UDP-glucuronosyltransferases (UGTs), located in the endoplasmic reticulum of liver cells, are an important family of enzymes, responsible for the biotransformation of several endogenous and exogenous chemicals, including therapeutic drugs. However, the phenomenon of 'latency', i.e., full UGT activity revealed by disruption of the microsomal membrane, poses substantial challenges for predicting drug clearance based on in vitro glucuronidation assays. This work introduces a microfluidic reactor design comprising immobilized human liver microsomes to facilitate the study of UGT-mediated drug clearance under flow-through conditions. The performance of the microreactor is characterized using glucuronidation of 8-hydroxyquinoline (via multiple UGTs) and zidovudine (via UGT2B7) as the model reactions. With the help of alamethicin and albumin effects, we show that conducting UGT metabolism assays under flow conditions facilitates in-depth mechanistic studies, which may also shed light on UGT latency.
Subject: 116 Chemical sciences
drug metabolism
glucuronidation
microreactors
enzyme immobilization
microfluidics
microfabrication
HUMAN UDP-GLUCURONOSYLTRANSFERASES
CYTOCHROME-P450 ENZYMES
FATTY-ACIDS
METABOLISM
ALBUMIN
PHOSPHOLIPIDS
EXPLANATION
FABRICATION
PREDICTION
KINETICS
317 Pharmacy
Drug metabolism
Glucuronidation
Microreactors
Enzyme immobilization
Microfluidics
Microfabrication
HUMAN UDP-GLUCURONOSYLTRANSFERASES
CYTOCHROME-P450 ENZYMES
FATTY-ACIDS
METABOLISM
ALBUMIN
PHOSPHOLIPIDS
EXPLANATION
FABRICATION
PREDICTION
KINETICS
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