Identification of interspecies difference in hepatobiliary transporters to improve extrapolation of human biliary secretion.
Increasing challenges include the application of in vitro/in vivo models for prediction of safety and pharmacokinetic profiles for the compounds entering drug development that are mainly secreted from bile. Species differences in biliary excretion have long been recognized and complicate the extrapolation of human pharmacokinetics from preclinical species or in vitro models. The currently available literature has been reviewed with a focus on drug-drug interactions mediated by hepatic drug transporters and the available tools for transporter assessments. Therefore, our incomplete understanding of interspecies differences and in vitro liver models poses a serious challenge in predicting human pharmacokinetics and/or safety profiles when the compounds are predominantly secreted from bile. This review outlines species differences in hepatobiliary secretion and the recent effort in understanding the absolute difference in hepatobiliary transporter expressions across species. In addition, understanding the expression of hepatobiliary transporters between in vitro hepatocyte models and in vivo to improve the prediction of biliary secretion is also discussed.
Lai
Yurong
Y
Pfizer Global Research & Development, Pfizer, Inc., Department of Pharmacokinetic, Dynamics, & Metabolism, St Louis Laboratory, 700 Chesterfield Parkway West, St Louis Chesterfield, MO 63017, USA. yurong.lai@pfizer.com
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D013045:Species Specificity
D004364:Pharmaceutical Preparations