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

Iiro Kiiski, Elisa Ollikainen, Sanna Artes, Päivi Järvinen, Ville Jokinen, Tiina Sikanen

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.

Originalspråkengelska
Artikelnummer105677
TidskriftEuropean Journal of Pharmaceutical Sciences
Volym158
Antal sidor9
ISSN0928-0987
DOI
StatusPublicerad - 1 mars 2021
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 116 Kemi
  • 317 Farmaci

Citera det här