Drug glucuronidation assays on human liver microsomes immobilized on microfluidic flow-through reactors
| Autor: | Tiina Sikanen, Iiro Kiiski, Sanna Artes, Ville Jokinen, Päivi Järvinen, Elisa Ollikainen |
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| Přispěvatelé: | University of Helsinki, Department of Chemistry and Materials Science, Aalto-yliopisto, Aalto University, Division of Pharmaceutical Chemistry and Technology, Tiina Sikanen / Chemical Microsystems Lab, Drug Research Program |
| Rok vydání: | 2021 |
| Předmět: |
Drug
PREDICTION media_common.quotation_subject 116 Chemical sciences Microfluidics FABRICATION Glucuronidation Pharmaceutical Science ALBUMIN 02 engineering and technology METABOLISM digestive system 030226 pharmacology & pharmacy EXPLANATION 03 medical and health sciences Glucuronides 0302 clinical medicine Biotransformation Microsomes Humans Enzyme immobilization Glucuronosyltransferase KINETICS media_common Drug metabolism Chemistry Endoplasmic reticulum glucuronidation Microreactors 021001 nanoscience & nanotechnology CYTOCHROME-P450 ENZYMES In vitro UGT2B7 PHOSPHOLIPIDS Pharmaceutical Preparations HUMAN UDP-GLUCURONOSYLTRANSFERASES Biochemistry 317 Pharmacy Microsomes Liver Microsome FATTY-ACIDS Microfabrication 0210 nano-technology |
| Zdroj: | European Journal of Pharmaceutical Sciences. 158:105677 |
| ISSN: | 0928-0987 |
| DOI: | 10.1016/j.ejps.2020.105677 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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