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Namandje' N. Bumpus
Namandje' N. Bumpus
Pharmacology and Molecular Sciences; Medicine - Division of Clinical Pharmacology
725 N. Wolfe Street
Baltimore MD 21205
Role of drug metabolism in non-nucleoside reverse transcriptase inhibitor-mediated toxicity
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 abrogate 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, To EE, Hendrix CW, Bumpus NN. Discovery of Genetic Variants of the Kinases That Activate Tenofovir in a Compartment-specific Manner. BioMedicine. 2015 Jul 9;2(9):1145-52. doi: 10.1016/j.ebiom.2015.07.008. eCollection 2015 Sep. PubMed PMID: 26501112; PubMed Central PMCID: PMC4588390
Lu Y, Fuchs EJ, Hendrix CW, Bumpus NN. CYP3A5 genotype impacts maraviroc concentrations in healthy volunteers. Drug Metab Dispos. 2014 Nov;42(11):1796-802. doi: 10.1124/dmd.114.060194. Epub 2014 Aug 12. PubMed PMID: 25117426; PubMed Central PMCID: PMC4201129.
Hersman EM, Bumpus NN. A targeted proteomics approach for profiling murine cytochrome P450 expression. J Pharmacol Exp Ther. 2014 May;349(2):221-8. doi: 10.1124/jpet.113.212456. Epub 2014 Mar 4. PubMed PMID: 24594750; PubMed Central PMCID: PMC3989799.
Avery LB, Bumpus NN. Valproic acid is a novel activator of AMP-activated protein kinase and decreases liver mass, hepatic fat accumulation, and serum glucose in obese mice. Mol Pharmacol. 2014 Jan;85(1):1-10. doi: 10.1124/mol.113.089755. Epub 2013 Oct 8. PubMed PMID: 24105977; PubMed Central PMCID: PMC3868906.
Cox PM, Bumpus NN. Structure-Activity Studies Reveal the Oxazinone Ring Is a Determinant of Cytochrome P450 2B6 Activity Toward Efavirenz. ACS Med Chem Lett. 2014 Sep 4;5(10):1156-1161. eCollection 2014 Oct 9. PubMed PMID: 25309681; PubMed Central PMCID: PMC4191608.