Metabolically-based, inhibitory drug-drug interactions are a major cause of morbidity and mortality in the therapeutic treatment of diseases. Although significant advances have been made in our understanding of the etiology of such adverse interactions, quantitative prediction of these events at early stages of drug development and clinical use remains elusive. Understanding the in vitro to in vivo relationships for interactions involving the major family of drug metabolizing enzymes, the cytochromes P450 (CYP), has been the focus of this Program Project since its inception. In the current proposal, we will examine four factors that we believe may underlie our inability to predict accurately changes in drug metabolism during polytherapy: (1) the relationship between inhibitor concentration in circulating blood and at the site of drug biotransformation (i.e., at the enzyme active site); (2) the relationship between substrate and inhibitor structure and binding affinity for the active site; (3) the dynamic interplay between simultaneous enzyme induction and inhibition from a single interacting agent; and (4) time-dependent and mechanism- based changes in intestinal first-pass metabolism following oral drug administration. In Project 1, we will determine for a series of CYP2C and 1A2 inhibitors, how inhibitor lipophilicity and plasma protein binding affect the concentration of the inhibitor at the enzyme active site and ultimately its in vivo potency. In Project 2, we will combine computational modeling with site-directed mutagenesis to identify the structural determinants that make a drug either a good inhibitor or good substrate of CYP2C9 and CYP2C19. In Project 3, we will determine how certain orally administered inhibitors of CYP3A4 preferentially alter intestinal, rather than hepatic, first-pass metabolism. Finally,, for Project 4, we will determine whether the paradoxical inhibitory and inductive effects of small, polar drug molecules on CYP2E1- and CYP2A6- dependent drug metabolism is mediated, in part, by their ability to interfere with the interaction between the enzyme and its important co- enzyme, cytochrome b/5. Overall, the studies proposed in this Program Project grant should provide major conceptual and methodological advances for the field of drug metabolism and improve our ability to develop safe, new therapeutic agents and manage existing drug therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM032165-17
Application #
6018578
Study Section
Special Emphasis Panel (ZGM1-PS-4 (02))
Project Start
1983-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Ho, Han Kiat; Chan, James Chun Yip; Hardy, Klarissa D et al. (2015) Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib. Drug Metab Rev 47:21-8
Chapron, Brian; Risler, Linda; Phillips, Brian et al. (2015) Reversible, time-dependent inhibition of CYP3A-mediated metabolism of midazolam and tacrolimus by telaprevir in human liver microsomes. J Pharm Pharm Sci 18:101-11
Hsiao, Peng; Unadkat, Jashvant D (2014) Predicting the outer boundaries of P-glycoprotein (P-gp)-based drug interactions at the human blood-brain barrier based on rat studies. Mol Pharm 11:436-44

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