The key role of transport proteins in the hepatic uptake and excretion of anionic drugs/metabolites is now widely recognized. Important progress during the current funding period has established that altered function of these transport proteins secondary to drug/toxicant interactions, disease states, or genetic predisposition may modulate systemic, intestinal (via bile) and/or hepatic exposure to drugs/metabolites and endogenous compounds, including bile acids. Such functional alterations have important therapeutic or toxicologic implications for some drugs. The long-term objective of this ongoing research program is to advance mechanistic understanding of how changes in transport function influence overall hepatobiliary disposition of anionic drugs/derived metabolites, and to develop tools to predict clinically-relevant outcomes of altered hepatic drug transport. The need for predictive probes/tools is imperative: research in the field of drug transport is still at an early stage, translation of this information to the clinical setting has been limited, and the potential for clinically- significant alterations in hepatic transport of drugs/metabolites is substantial. A multi-experimental approach incorporating state-of-the-art techniques including sandwich-cultured primary rat and human hepatocytes coupled with RNAi to selectively knock down transport proteins, in vitro expression systems, isolated perfused livers from wild-type and transport protein-deficient rodents, an in vivo human protocol using an MRP2 imaging agent as a phenotypic probe to assess hepatic drug transport interactions, and pharmacokinetic modeling/simulation will be employed to elucidate mechanisms and consequences of altered hepatic transport of model anionic drugs/metabolites. Proposed studies will address three key issues: 1) implications of the multiplicity of drug transport proteins on hepatobiliary drug/metabolite disposition in response to impaired transport function, 2) role of transport proteins in drug-induced liver injury, and 3) development of probes/tools to assess transport protein function. Elucidating mechanisms of altered hepatic drug transport, and identifying the functional consequences of those alterations, are prerequisite to exploiting these processes to achieve desirable clinical outcomes.
Transport proteins in the liver remove many drugs from the body, and may significantly influence drug efficacy or toxicity. This research will clarify how these transport proteins work in concert to control accumulation and excretion of drugs in the liver, and the impact of impaired transport function (e.g., by drugs or disease). An important goal is to develop tools to predict and assess altered drug transport in humans. Results of these studies will impact drug development, improve outcomes of drug therapy, and help prevent drug-induced liver injury.
|Kaullen, Josh D; Owen, Joel S; Brouwer, Kim L R et al. (2018) Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers. Anesthesiology 128:1107-1116|
|Kenna, J Gerry; Taskar, Kunal S; Battista, Christina et al. (2018) Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective. Clin Pharmacol Ther 104:916-932|
|Guo, Yingying; Chu, Xiaoyan; Parrott, Neil J et al. (2018) Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches. Clin Pharmacol Ther 104:865-889|
|Brock, William J; Beaudoin, James J; Slizgi, Jason R et al. (2018) Bile Acids as Potential Biomarkers to Assess Liver Impairment in Polycystic Kidney Disease. Int J Toxicol 37:144-154|
|Guo, Cen; Yang, Kyunghee; Liao, Mingxiang et al. (2017) Prediction of Hepatic Efflux Transporter-Mediated Drug Interactions: When Is it Optimal to Measure Intracellular Unbound Fraction of Inhibitors? J Pharm Sci 106:2401-2406|
|Woodhead, Jeffrey L; Brock, William J; Roth, Sharin E et al. (2017) Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors. Toxicol Sci 155:61-74|
|Ali, Izna; Welch, Matthew A; Lu, Yang et al. (2017) Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay. Eur J Pharm Sci 103:52-59|
|Thakkar, Nilay; Slizgi, Jason R; Brouwer, Kim L R (2017) Effect of Liver Disease on Hepatic Transporter Expression and Function. J Pharm Sci 106:2282-2294|
|Ali, Izna; Slizgi, Jason R; Kaullen, Josh D et al. (2017) Transporter-Mediated Alterations in Patients With NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate. Clin Pharmacol Ther :|
|Gonzalez, Daniel; Rao, Gauri G; Bailey, Stacy C et al. (2017) Precision Dosing: Public Health Need, Proposed Framework, and Anticipated Impact. Clin Transl Sci 10:443-454|
Showing the most recent 10 out of 108 publications