Department Affiliation: Primary: Medicine; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Johns Hopkins University
Rank: Professor
Telephone Number: 410-955-9712
Fax Number: 410-955-9708
E-mail address: flex@jhmi.edu
School of Medicine Address: 503 Osler Building, 600 N. Wolfe St., Baltimore, MD 21287-5554
Basic and clinical pharmacology of antiretroviral drugs; HIV protease inhibitors and entry inhibitors
A. Laboratory activities include the use of accelerator mass spectrometry (AMS) techniques to measure intracellular drugs and drugs metabolites. AMS is a highly sensitive method for detecting tracer amounts of radio-labeled molecules in cells, tissues, and body fluids. We have been able to measure intracellular zidovudine triphosphate (the active anabolite of zidovudine) in peripheral blood mononuclear cells from healthy volunteers given small doses of 14C-zidovudine, and have directly compared the sensitivity of AMS to traditional LC/MS methods carried out in our laboratory.
B. Clinical research activities investigate the clinical pharmacology of new anti-HIV therapies and drug combinations. Specific drug classes studied include HIV reverse transcriptase inhibitors, protease inhibitors, entry inhibitors (selective CCR5 and CXCR4 antagonists), and integrase inhibitors. Scientific objectives of clinical studies include characterization of early drug activity, toxicity, and pharmacokinetics. Additional objectives are characterization of pathways of drug metabolism, and identification of clinically significant harmful and beneficial drug interactions mediated by hepatic and intestinal cytochrome P450 isoforms.
Representative Publications:
- Lee LS, Stephenson KK, Fahey JW, Parsons TL, Lietman PS, Andrade AS, Lei X, Yun H, Soon GH, Shen P, Danishefsky S, Flexner C. Induction of chemoprotective phase 2 enzymes by ginseng and its components. Planta Medica 2009; 75:1-5. Pub Med Reference
- Tsibris AMN, Korber B, Arnaout R, Russ R, Lo C-C, Leitner T, Gaschen B, Theiler J, Paredes R, Su Z, Hughes MD, Gulick RM, Greaves W, Coakley E, Flexner C, Nusbaum C, Kuritzkes DR. Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS ONE 2009; 4(5): e5683. Pub Med Reference
- Flexner C. HIV drug development: the next 25 years. Nature Reviews Drug Discovery 2007; 6: 959-966. [Reprinted in Nature Biotechnology Antivirals Supplement 2008; 26: S39-S46.] Pub Med Reference.
Tsibris AMN, Sagar M, Gulick RM, Su Z, Hughes M, Greaves W, Subramanian M, Flexner C, Leopold KE, Coakley E, Kuritzkes DR. In vivo emergence of vicriviroc resistance in an HIV-1 subtype C-infected subject. J Virol 2008; 82: 8210-8214. Pub Med Reference.
Lee LS, Wise SD, Chan C, Parsons TL, Flexner C, Lietman PS. Possible differential induction of phase 2 enzyme and antioxidant pathways by American ginseng, Panax quinquefolius. J Clin Pharmacol 2008; 48: 599-609. Pub Med Reference.
Bakshi RP, Hamzeh F, Frank I, Eron JJ, Bosch RJ, Rosenkranz SL, Cramer YS, Ussery M, Flexner C. Effect of hydroxyurea and dideoxyinosine on intracellular 3’-deoxyadenosine-5’-triphosphate concentrations in HIV-infected patients. AIDS Res Hum Retroviruses 2007; 23: 1360-1365. Pub Med Reference.
Gulick RM, Su Z, Flexner C, Hughes M, Skolnik PR, Wilkin TJ, Gross R, Krambrink A, Coakley E, Greaves W, Zolopa A, Reichman R, Godfrey C, Hirsch M, Kuritzkes DR for the ACTG 5211 Team. Phase II study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: ACTG 5211. J Infect Dis 2007; 196:178-180. Pub Med Reference.
Stone ND, Dunaway SB, Flexner C, Tierney C, Calandra GB, Becker S, Cao Y-J, Wiggins IP, Conley J, MacFarland RT, Park J-G, Lalama C, Snyder S, Kallungal B, Klingman KL, Hendrix CW. Multiple dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects (ACTG A5191). Antimicrob Agents Chemother 2007; 51: 2351-2358. Pub Med Reference.
- Nettles, R.E., Kieffer, T.L., Kwon, P., Monie, D., Han, Y., Adnan, S., Parsons, T., Cofrancesco, J., Gallant, J.E., Quinn, T., Jackson, B., Flexner, C., Carson, K., Ray, S., Persaud, D., and Siliciano, R.F. Intermittent HIV-1 viremia and the evolution of drug resistance in patients on highly active antiretroviral therapy, JAMA 293:817-829, 2005. Pub Med Reference.
- Rufo, P., Lin, P.W., Andrade, A., Jiang, L., Rameh, L., Flexner, C., Alper, S.L., and Lencer, W.I. Diarrhea-associated HIV-1 aspartyl protease-inhibitors potentiate muscarinic activation of Cl- secretion byT84 cells via prolongation of cytosolic Ca2+ signaling, Am. J. Physiol.Cell. Physiol. 286:998-1008, 2004. Pub Med Reference.
Other graduate programs in which Dr. Flexner participates:
