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School of Medicine
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Department Affiliation: Primary: Medicine, Division of Clinical Pharmacology;
Secondary: Pharmacology and Molecular Sciences
Degree: Ph.D., University of Michigan
Rank: Associate Professor; Associate Dean for Institutional and Student Equity
School of Medicine Address: Biophysics 307-A, 725 North Wolfe Street, Baltimore, MD 21205
Drug Metabolism and preclinical drug development; small molecule mass spectrometry; targeted metabolomics; antiviral drug-induced toxicity; modulation of cellular signaling pathways by reactive metabolites.
Our laboratory uses mass spectrometry and molecular pharmacology based approaches to investigate the biotransformation of clinically used drugs by the cytochromes P450s. The cytochromes P450 are crucial to drug disposition as they are responsible for the metabolism of an estimated 75% of currently marketed drugs. Cytochrome P450-mediated biotransformation of drugs most often results in the production of hydrophilic metabolites that can be readily excreted from the body; however, in certain instances toxic metabolites are formed that can stimulate cell death and organ failure. Research in our laboratory focuses on defining a role for cytochrome P450-dependent metabolites in the drug-induced acute liver failure that is associated with certain antiviral drugs used to treat HIV and hepatitis C. To approach this, we develop novel mass spectrometry assays to measure and discover drug metabolites. In addition, we isolate these metabolites and probe their pharmacology and toxicology using both in vitro and in vivo models. In doing so, we examine modulation of cellular signaling pathways by these metabolites using molecular techniques and mass spectrometry-based metabolomics to spur discovery of biomarkers and novel therapeutic targets for drug-induced liver failure. Further, once we have elucidated the chemical structure of a toxic metabolite we test whether blocking the site of metabolism can inhibit the toxicity without altering the pharmacologic activity of the drug. The long-term goal of our laboratory is gain information that can be used to develop next generation therapies that are devoid of these toxic events by preventing the formation of a toxic metabolite and/or by developing strategies for preventing toxicity using concomitant therapy.
Lade JM, Avery LB, Bumpus NN. Human Biotransformation of the Non-nucleoside Reverse Transcriptase Inhibitor Rilpivirine and a Cross Species Metabolism Comparison. Antimicrob Agents Chemother. Oct;57(10):5067-79, 2013. Pub Med Reference
Hendrix C, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, Salata R, Soto-Torres L, Patterson K, Minnis AA, Gandham S, Gomez K, Richardson BA and Bumpus NN. 2013. MTN-001: Randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS One 8(1):e55013. Pub Med Reference
Avery LB, Vanausdall JL, Hendrix CW and Bumpus NN. Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma and Cerebrospinal Fluid. Drug Metabolism and Disposition 41(2):422-9, 2013. Pub Med Reference
Anton PA, Cranston RD, Kashuba A, Hendrix C, Bumpus NN, Richardson-Harman N, Elliott J, Janocko L, Khanukhova E, Dennis RA, Cumberland WG, Ju C, Carballo-Diéguez A, Mauck C, McGowan IM. RMP-02/MTN-006: A Phase 1 Rectal Safety, Acceptability, Pharmacokinetic and Pharmacodynamic Study of Tenofovir 1% Gel Compared to Oral Tenofovir Disoproxil Fumerate. AIDS Research and Human Retroviruses 28(11):1412-21, 2012. Pub Med Reference
Lu Y, Hendrix CW and Bumpus NN. 2012. Cytochrome P450 3A5 Plays a Prominent Role in the Oxidative Metabolism of the Anti-HIV Drug Maraviroc. Drug Metabolism and Disposition 40(12):2221-30, 2012. Pub Med Reference
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C; the Partners PrEP Study Team. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. New England Journal of Medicine 367(5):399-410, 2012. Pub Med Reference
Yanakakis, L.J. and Bumpus, NN. Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metabolism and Disposition 40(4):803-814, 2012. Pub Med Reference
Bumpus, NN. Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicology and Applied Pharmacology 257(2):227-234, 2011. Pub Med Reference
Other graduate programs in which Dr. Bumpus participates: