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Abstract
Grant Number: 1R21GM075900-01 Project Title: Transporter-Enzyme Interplay Evaluation via Microfluidiic HTS Cell Culture Device
PI Information: Name Title BENET, LESLIE Z. leslie.benet@ucsf.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): Because of numerous past failures, it is the belief of many pharmaceutical scientists that animal models are not useful in predicting human DMPK (drug metabolism and pharmacokinetics) and toxicology. This has promoted initiatives to advance NMEs (new molecular entities) into man as soon as possible with a deemphasis of animal work. Although there can be marked advantages to evaluation of NMEs in humans early in drug development, we do not believe that this is the most efficient or most effective way to select the DMPK-optimal molecule from many potential candidate compounds. We hypothesize that the poor predictability of animal models for highly metabolized compounds (approximately 70% of drugs on the market) is due to our nascent understanding of how to incorporate transporters, both absorptive and efflux, into predictive models of drug metabolism, and this lack of understanding of transporter-enzyme interplay renders traditional drug disposition theory simplistic and inadequate, which accounts for the poor predictability. However, most importantly we lack a simple high-throughput preclinical tool to characterize transporter enzyme interplay that conveniently allows human-animal comparisons. In this application, we describe a novel preclinical tool, the microfluidic cell culture biochip in development by the Hurel Corporation and propose studies to test the applicability of this system to address the issues of concern as outlined in 10 specific aims. We will characterize hepatic and enterocyte transporter-enzyme interplay in the Hurel system, initially separately and then combined, utilizing cultured rat and human hepatocytes and enterocytes for Class 1 and Class 2 highly metabolized compounds. These data will be compared with rat liver and intestinal perfusion, rat and human hepatocyte/enterocyte and microsome studies and whole animal iv dosing pharmacokinetics studies carried out predominantly external to this application. A major focus of the work will be to test the concordance of the Hurel device results with the more laborious animal and human studies and to develop models that will allow prediction of animal preclinical DMPK using the Hurel microfluidic cell culture biochips, as well as address the deficiency of our present models of drug elimination that do not adequately consider transporter-enzyme interplay in drug disposition.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
biosensor device, enzyme substrate complex, microarray technology, microfluidics, technology /technique development, transport protein
chemical elimination, drug metabolism, gastrointestinal drug absorption, liver cell, microsome, pharmacokinetics
NIH Roadmap Initiative tag, animal tissue, bioengineering /biomedical engineering, high throughput technology, human tissue, laboratory rat, tissue /cell culture
Institution: UNIVERSITY OF CALIFORNIA SAN FRANCISCO 3333 California St., Ste 315 SAN FRANCISCO, CA 941430962 Fiscal Year: 2006 Department: BIOPHARMACEUTICAL SCIENCES Project Start: 02-JUN-2006 Project End: 31-MAY-2009 ICD: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES IRG: ZGM1