Metabolically-based drug-drug interactions are a major cause of morbidity and mortality in the therapeutic treatment of disease. Although significant advances have been made in our understanding of the etiology of such adverse drug reactions, quantitative prediction of these events at early stages of drug development and clinical use remains elusive. This Program Project Grant focuses on understanding the in vitro to in vivo relationships for drug-drug interactions involving the human cytochrome P450 family of enzymes and drug transporters. In the current proposal, we will investigate several emerging factors that complicate our ability to accurately predict changes in drug metabolizing enzyme and drug transporter activity that result from the co-administration of multiple interacting species; (i) non-hyperbolic kinetics and cooperative ligand binding to human P450s, (ii) sequential oxidative metabolism and the formation of metabolic-intermediate (MI) complexes, (iii) the variable contribution made by Type II binding to inhibitor Ki, (iv) the role(s) of drug transporters such as the human OCTs, MDRs and MRPs, and (v) the interplay of drug-metabolizing enzymes and drug transporters in drug interactions associated with induction mechanisms. In Project 1 we will synthesize novel high affinity inhibitors for human CYP2C enzymes and combine this with site-directed mutagenesis studies to enable construction of discriminating computational and structural models for the prediction of inhibitor Ki. In Project 2, we will explore the mechanistic basis for 'allosteric' kinetic behavior with CYP3A4, towards a variety of ligands including caffeine, acetaminophen, pyrene and hypericin using fluorescence and NMR-based approaches. In Project 3, we will explore reasons for the discrepancy between in vivo and in vitro Kis for the test compounds, itraconazole and fluvoxamine and develop new kinetic models for sequential metabolism and MI complex formation with macrolides and antidepressants. In Project 4 we will determine the molecular and genetic factors that influence, both in vivo and in vitro, the magnitude and spectrum of human P450 enzymes and drug transporters induced by the anti-HIV protease inhibitors, nelfinavir and ritonavir. Collectively, these studies should provide new conceptual and practical tools to achieve quantitative predictions of drug-drug interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM032165-22
Application #
6787678
Study Section
Special Emphasis Panel (ZGM1-PS-9 (01))
Program Officer
Okita, Richard T
Project Start
1983-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
22
Fiscal Year
2004
Total Cost
$1,482,179
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wong, Timothy; Wang, Zhican; Chapron, Brian D et al. (2018) Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-Sulfate, a Major Circulating Vitamin D Metabolite in Humans. Drug Metab Dispos 46:367-379
Shirasaka, Y; Chaudhry, A S; McDonald, M et al. (2016) Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content. Pharmacogenomics J 16:375-87
Manoj, Kelath Murali; Parashar, Abhinav; Gade, Sudeep K et al. (2016) Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes. Front Pharmacol 7:161
Stamper, Brendan D; Garcia, Michael L; Nguyen, Duy Q et al. (2015) p53 Contributes to Differentiating Gene Expression Following Exposure to Acetaminophen and Its Less Hepatotoxic Regioisomer Both In Vitro and In Vivo. Gene Regul Syst Bio 9:1-14
McDonald, Matthew G; Au, Nicholas T; Rettie, Allan E (2015) P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms. Drug Metab Dispos 43:1661-9
Chaudhry, Amarjit S; Prasad, Bhagwat; Shirasaka, Yoshiyuki et al. (2015) The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles. Drug Metab Dispos 43:1226-35
Liu, Li; Collier, Ann C; Link, Jeanne M et al. (2015) Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study. Drug Metab Dispos 43:1795-804
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
Hardy, Klarissa D; Wahlin, Michelle D; Papageorgiou, Ioannis et al. (2014) Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab Dispos 42:162-71

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