I am originally from the Kansas City area, and currently live in Shawnee, KS. For several years now I have worked with Andrew Parkinson (formerly a tenured professor in the department) at XenoTech, LLC, where I worked as a study director for in vitro drug-drug interaction studies to support IND and NDA submissions of drug candidates from both biotech and mid-size to large pharmaceutical companies. I have completed the IGPBS core curriculum and have now started my first full year of course work in the department
My research interests include the CYP-mediated oxidative metabolism of glucuronides and other conjugates, as well as inhibition of CYP enzymes by these conjugates. My work in this area began with the discovery that the acyl-glucuronide of gemfibrozil is a metabolism-dependent inhibitor of CYP2C8, and in part explains the mechanism of the fatal interactions between gemfibrozil and the CYP2C8 substrate, cerivastatin, a cholesterol-lowering statin that was withdrawn from the market largely because of this severe adverse interaction. This finding was unusual because gemfibrozil most potently inhibits CYP2C9 in vitro, which is expected given that gemfibrozil is a small acidic molecule. However, gemfibrozil does not increase systemic exposure to warfarin (a CYP2C9 substrate with a narrow therapeutic index). Glucuronidation of gemfibrozil, which is the predominant metabolic pathway in vivo, converts this CYP2C9 inhibitor into a CYP2C8 substrate and metabolism-dependent inhibitor of this important xenobiotic-metabolizing enzyme. Other compounds are also first glucuronidated and subsequently oxidized by CYP2C8, including diclofenac, licofelone and estradiol. Such examples of “Phase I” metabolism occurring after “Phase II” metabolism can be easily overlooked in the clinic depending on sample handling because glucuronides can be hydrolyzed and release oxidative metabolites either prior to or after collection of samples. Such a scenario can potentially lead to the erroneous conclusion that a drug was directly hydroxylated rather than first being glucuronidated. Under the supervision of Andrew Parkinson, I plan to continue my search for and characterization of other drugs that follow this metabolic scheme, and for glucuronides or other conjugates that inhibit CYP enzymes with the aim of providing mechanistic insight into other, as yet unexplained, drug-drug interactions.
Selected Publications
Ogilvie BW, Usuki E, Yerino P and Parkinson A. (2008) In Vitro Approaches for Studying the Inhibition of Drug-Metabolizing Enzymes and Identifying the Drug-Metabolizing Enzymes Responsible for the Metabolism of Drugs (Reaction Phenotyping) with Emphasis on Cytochrome P450, in: Drug-Drug Interactions (Rodrigues AD, ed.), Informa Healthcare, New York, 231-358.
Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, Parkinson A. (2006) Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: Implications for drug-drug interactions. Drug Metab Dispos 34(1):191-197.
Ye C, Sweeny D, Sukbuntherng J, Zhang Q, Tan W, Wong S, Madan A, Ogilvie B, Parkinson A, Antonian L. (2006) Distribution, metabolism, and excretion of the anti-angiogenic compound SU5416. Toxicol In Vitro. 20(2): 154-62.
Contact Information
Brian Ogilvie
Department of Pharmacology, Toxicology, and Therapeutics
The University of Kansas Medical Center
XenoTech, LLC
16825 W 116th St.
Lenexa, KS 66219
Phone: (913) 227-7137
Fax: (913) 227-7100
E-Mail: bogilvie@kumc.edu or bogilvie@xenotechllc.com
Updated 11/13/08
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The University of Kansas Medical Center