On receiving the Best Poster Award
Meiji Pharmaceutical University
I am very honored to receive the Best Poster Award at the 37th Annual Meeting of the Japanese Pharmacokinetic Society for the presentation entitled “Usefulness of Simultaneous Humanization of PXR and CYP3A for Drug Interaction Analysis in Rats”. I would like to express my sincere gratitude to the judges and all the people involved in the Japanese Society of Pharmacokinetics and Pharmacodynamics.
Cytochrome P450 3A (CYP3A) is an important drug-metabolizing enzyme that is a substrate for many drugs and is a factor in various drug-drug interactions. We have focused on the interspecies differences in CYP3A between animals and have generated CYP3A humanized rats that lack endogenous Cyp3a and have been transfected with human CYP3A. The humanized rats, in which not only the coding region but also the transcriptional regulatory region has been introduced, show CYP3A tissue expression distribution and induction of expression by inducers similar to that in humans. On the other hand, it was necessary to overcome the species differences in the nuclear receptors involved in CYP3A induction in order to evaluate CYP3A induction more appropriately. In this study, we generated rats in which the nuclear receptor pregnane X receptor (PXR) was humanized in addition to CYP3A (PXR/CYP3A humanized rats), and investigated the response of CYP3A4 to rifampicin, a human PXR-selective ligand, and its usefulness as an in vivo drug-drug interaction We investigated the response of CYP3A4 to rifampicin, a human PXR-selective ligand, and its usefulness as a model for in vivo drug interaction analysis.
We found that CYP3A4 expression and activity in the liver and small intestine of PXR/CYP3A humanized rats increased in a rifampicin dose-dependent manner. Subsequently, in vivo CYP3A4 activity was analyzed by administering a substrate for CYP3A4. In vivo CYP3A4 activity was increased in PXR/CYP3A humanized rats, but not in PXR unchanged rats. Furthermore, in vivo CYP3A4 activity was decreased in PXR/CYP3A humanized rats upon administration of a CYP3A4 inhibitor. These results suggest that PXR/CYP3A humanized rats may be applicable to the prediction of complex drug-drug interactions involving confounding induction and inhibition of CYP3A4 in the clinical setting.
Finally, we would like to express our deepest gratitude to Dr. Kaoru Kobayashi and Dr. Yasuhiro Kazuki of Tottori University for their guidance in conducting this study, and to all the students and collaborators for their cooperation in this research.