? 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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21GM075900-03
Application #
7429824
Study Section
Special Emphasis Panel (ZGM1-PPBC-0 (TX))
Program Officer
Okita, Richard T
Project Start
2006-06-02
Project End
2009-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$354,877
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Garrison, Kimberly L; Sahin, Selma; Benet, Leslie Z (2015) Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS. J Pharm Sci 104:3229-35
Broccatelli, Fabio; Cruciani, Gabriele; Benet, Leslie Z et al. (2012) BDDCS class prediction for new molecular entities. Mol Pharm 9:570-80
Broccatelli, Fabio; Larregieu, Caroline A; Cruciani, Gabriele et al. (2012) Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev 64:95-109
Reyes, Maribel; Benet, Leslie Z (2011) Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics. J Pharm Sci 100:3831-42
Benet, Leslie Z; Broccatelli, Fabio; Oprea, Tudor I (2011) BDDCS applied to over 900 drugs. AAPS J 13:519-47
Frymoyer, A; Shugarts, S; Browne, M et al. (2010) Effect of single-dose rifampin on the pharmacokinetics of warfarin in healthy volunteers. Clin Pharmacol Ther 88:540-7
Benet, Leslie Z (2010) Predicting drug disposition via application of a Biopharmaceutics Drug Disposition Classification System. Basic Clin Pharmacol Toxicol 106:162-7
Benet, Leslie Z (2010) Clearance (nee Rowland) concepts: a downdate and an update. J Pharmacokinet Pharmacodyn 37:529-39
Grover, Anita; Benet, Leslie Z (2009) Effects of drug transporters on volume of distribution. AAPS J 11:250-61
Shugarts, Sarah; Benet, Leslie Z (2009) The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res 26:2039-54

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