Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 109, Issue 5, Pages 1186-1188Publisher
WILEY
DOI: 10.1002/cpt.2019
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Funding
- Personalized Medicine - Diagnostics and Therapy project from the TACR agency [TN01000013]
- pre-application research of innovative drugs and medical technologies project - European Union [CZ.02.1.01/0.0/0.0/18_069/001004 6]
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This study utilized 3D human hepatocyte spheroids as a model for CYP450 enzyme induction, demonstrating high sensitivity and specificity. The authors identified a noncanonical PXR-mediated CYP3A4 induction mechanism, highlighting the importance of using 3D primary human hepatocyte spheroids in preclinical induction testing.
Hendriks and coworkers(1) used 3D human hepatocytes spheroids as a novel model for CYP450 enzyme induction showing 100% sensitivity and 100% specificity when testing 12 clinically known CYP3A4 inducers. Importantly, the authors describe a noncanonical pregnane X receptor (PXR)-mediated CYP3A4 induction mechanism in the model with a compound (AZD1208), which failed in phase I clinical studies due to (auto)induction of CYP3A4 metabolism. These findings warrant the model of 3D primary human hepatocyte (PHH) spheroids in preclinical induction testing.
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