ADME Assays in Drug Discovery and Preclinical Drug Development Research at TRND/NCATS/NIH

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCATS	CHEM-10

Authors

• KL.T. Nguyen
• E.H. Kerns
• X. Xin
• J.C. Mckew

Abstract

The ADME (Absorption, Distribution, Metabolism, and Elimination)Bioanalytical group has been established and is now developing at NCATS in TRND. In this group, we focus on assessing in vitro physicochemical and metabolic properties, such as solubility, permeability, metabolic stability, and in vivo pharmacokinetics during drug discovery process. The goal is to optimize the pharmacokinetics of drug candidates in parallel with optimizing their intrinsic activity. This has been shown to save research costs and time from clinical candidate failure, due to poor in vivo exposures and un-desirable pharmacokinetic profiles. We implemented physicochemical methods: kinetic solubility (µg/mL), and PAMPA permeability (10 -6 cm/s). These values provide information affecting absorption of drug candidates. We implemented rat liver microsomal metabolic stability assay (t 1/2, minute). These values provide information affecting metabolic drug clearance. We also implemented plasma/tissue bioanalysis to provide pharmacokinetic properties of candidates: bioavailability (%F), exposure (AUC), clearance (Cl), half-life (t 1/2) and volume of distribution (Vd), using different administration routes: oral (PO) and intravenous (IV). In order to evaluate and manage the large number of compounds of interest, we developed and implemented the high throughput in vitro ADME screen assays by applying the latest analytical and automation technologies: LC-MS/MS and lab robots.

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