Prediction of Cytochrome 450 Mediated Drug-Drug Interactions by Three-Dimensional Cultured Hepatocytes

C.      Shen; Q.      Meng

Abstract

Cytochrome P450 (CYP) inhibition and induction are the key mechanisms in drug-drug interactions which should be avoided in clinic for the uncertain influence on the efficacy and safety of drug co-administration. The CYPmediated drug-drug interactions urgently need to be predicted by in vitro models before animal and clinical trials, while the primary hepatocytes may represent the most appropriate experimental system by now. However, traditional twodimensional (2D) culture of hepatocyte monolayer, regardless of the good facilitation and repeatability, rapidly loses its CYP-inducibility during short-term culture due to the deviated microenvironments from in vivo. Also, 2D culture did not reproduce the CYP-inhibition mediated hepatotoxicity in drug co-administration. Recently, three-dimensional (3D) cultured hepatocytes have been recognized as the promising models for predicting in vivo drug-drug interactions. The 3D cultures such as sandwich and gel entrapped hepatocytes showed the comparable response to CYP inhibitors and inducers as in vivo and well reflected the inhibitor/inducer mediated hepatotoxicity. In this regard, this review, for the first time, compares the effect of 2D and 3D hepatocyte cultures on reflecting CYP-mediated drug-drug interactions in vivo. And the advantage of 3D cultured hepatocytes on predicting in vivo CYP-induction/inhibition will be particularly discussed.

Keywords: Drug-drug interactions, 3D culture, CYP 450, induction, inhibition, prediction.

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