3D Spheroids of Primary Human Hepatocytes: An In Vitro Model That Will Make Pharmacotherapy Safer?

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.

Automated summary

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.