Desirable drug ADME (Absorption, Disposition, Metabolism and Elimination) properties are key determinants of a drug's to safety and efficacy. Unfortunately, poor ADME and Toxicity attributes have caused more drug failures than any other factors. There is a pressing need for better in vitro predictive ADME tools to augment the decade-old animal studies which do not always predict clinical results in the human. The overall goal of this project is to ascertain whether in vivo drug ADME properties could be explained and predicted based on drugs'in vitro interactions with transporter proteins, which have been demonstrated to play significant roles in every aspect of drug ADME, along with metabolic enzyme interaction and other drug physicochemical properties. The initial Phase I work will start with examining the roles of major liver transporters on hepatic disposition of drugs, through testing a panel of drugs against these transporters;novel in vitro models will be created for studying the effects of transporters-CYP interplay on hepatic drug metabolism;finally, correlations between in vitro data and clinical disposition and metabolism information will be established. Future study would extend the scope to other major tissues/organs with aims to explain and predict drug ADME properties and drug-drug interactions (DDI) based on in vitro transporter studies and other drug physicochemical properties.
Success of this project will benefit public health by facilitating discovery and development of drugs for treating various formidable diseases, particularly CNS diseases and cancer, through enhancing drug efficacy by increasing targeted drug delivery to diseased tissues, and through improving drug safety by reducing adverse drug effects due to unwanted tissue distribution and drug-drug interactions.
|Zheng, Yi; Chen, Xijing; Benet, Leslie Z (2016) Reliability of In Vitro and In Vivo Methods for Predicting the Effect of P-Glycoprotein on the Delivery of Antidepressants to the Brain. Clin Pharmacokinet 55:143-67|
|Zheng, Yi; Benet, Leslie Z; Okochi, Hideaki et al. (2015) pH Dependent but not P-gp Dependent Bidirectional Transport Study of S-propranolol: The Importance of Passive Diffusion. Pharm Res 32:2516-26|
|Ellens, Harma; Deng, Shibing; Coleman, Joann et al. (2013) Application of receiver operating characteristic analysis to refine the prediction of potential digoxin drug interactions. Drug Metab Dispos 41:1367-74|
|Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas et al. (2013) Variability in P-glycoprotein inhibitory potency (IC??) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria. Drug Metab Dispos 41:1347-66|
|Liu, Wei; Okochi, Hideaki; Benet, Leslie Z et al. (2012) Sotalol permeability in cultured-cell, rat intestine, and PAMPA system. Pharm Res 29:1768-74|