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 encompass the basic pharmacology of HIV protease inhibitors. We are investigating the role of transmembrane drug transporters, including P-glycoprotein and the multidrug resistance-1 protein, in regulating intracellular drug concentrations and modulating the infectivity of HIV. HIV mutants are used to characterize the mechanism of action of new inhibitors, including differential effects on protein processing. Plasma protein binding properties of a number of antiretroviral agents have been used to characterize the binding process, including important regulatory pathways for alpha1-acid glycoprotein (AAG), the role of carbohydrates in protein binding, and development of expression vectors for mutational analysis of AAG.
B. Clinical research activities investigate the clinical pharmacology of new anti-HIV therapies and combinations. Specific approaches studied include the polysulfated polysaccharide dextran sulfate; the nucleoside analog deoxyfluorothymidine (FLT); recombinant bacterial toxins (CD4 Pseudomonas exotoxin and interleukin-2/ diphtheria toxin); a selective HIV tat antagonist; recombinant CD4 electroinserted autologous human red blood cells; an anti-gag antisense oligonucleotide; and the peptidomimetic HIV protease 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:
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 by T84 cells via prolongation of cytosolic Ca2+ signaling, Am. J. Physiol. Cell. Physiol. 286:998-1008, 2004. Pub Med Reference
Hendrix, C.W., Collier, A.C., Lederman, M.M., Schols, D., Pollard, R.B., Brown, S., Jackson, J.B., Coombs, R.W., Glesby, M.J., Flexner, C.W., Bridger, G.J., Badel, K., MacFarland, R.T., Henson, G.W., and Calandra, G., for the AMD3100 Study Group. Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection, J. Acquir. Immune Defic. Syndr. 37:1253-1262, 2004. Pub Med Reference
- Washington, C.B., Flexner, C., Sheiner, L.B., Rosenkranz, S.L., Segal, Y., Aberg, J.A., and Blaschke, T.F., for the ACTG 378 Study Team. Effect of simultaneous versus staggered dosing on pharmacokinetic interactions of protease inhibitors, Clin. Pharmacol. Ther. 73:406-416, 2003. Pub Med Reference
- Lu, J.-F. , Blaschke, T.F., Flexner, C., Rosenkranz, S., and Sheiner LB. Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration, Drug Metab. Disposit. 30: 1455-1461, 2002. Pub Med Reference
- Speck, R.R., Yu, X.-F., Hildreth, J.E., and Flexner, C. Differential effects of P-glycoprotein and multidrug resistance protein-1 on productive HIV infection, J Infect Dis. 186: 332-340, 2002. Pub Med Reference
- Dowell, P., Flexner, C., Kwiterovich, P.O., and Lane, M.D. Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors, J. Biol. Chem. 275: 41325-41332, 2000. Pub Med Reference
- Speck, R.S., Flexner, C., Tian, C.-J., and Yu, X.-F. Comparison of human immunodeficiency virus type 1 Pr55Gag and Pr160Gag-Pol processing intermediates that accumulate in primary and transformed cells treated with peptidic and non-peptidic protease inhibitors, Antimicrob Agents Chemother, 44:1397-1403, 2000. Pub Med Reference
- Finzi, D., Blankson, J., Siliciano, J.D., Margolick, J.B., Chadwick, K., Pierson, T, Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T.C., Chaisson, R.E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., Siliciano, R.F. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy, Nature Med., 5:512-517, 1999. Pub Med Reference
- Other graduate programs in which Dr. Flexner participates:
- BCMB Program
