Dr. Elmquist's laboratory studies the biochemical and physiological determinants of drug absorption, distribution and elimination. Recent studies have focused on the role of drug transport proteins in drug distribution to target tissues. Current research examines the effect that various multidrug resistance proteins (drug efflux pumps), such as the p-glycoprotein (P-gp), and similar efflux proteins, the multidrug-resistance associated proteins (MRPs), have on drug targeting to the central nervous system (CNS). The use of molecular biology, in vitro models, intracerebral microdialysis, and gene knockout animals have been essential tools in this research.
An important project currently underway is the search for strategies to improve the delivery of highly-active anti-retroviral therapy (HAART) to the brain using novel drug delivery systems. Unique animal models of HIV1 encephalitis and transgenic mice deficient in one or more of the genes that encode drug efflux transport proteins are employed to determine both drug distribution and drug efficacy in the CNS. Similar studies are underway to examine the determinants of anticancer drug permeability in the blood-brain barrier. The effective treatment of brain tumor is limited by inadequate delivery of the chemotherapy to the CNS. Some anticancer drugs are substrates for the drug efflux proteins found in these barriers, and therefore an opportunity to improve the targeted bioavailability to the CNS tumor may exist.
Long term objectives of Dr. Elmquist's research include examining expression and regulation of transport systems in key tissues that influence drug disposition, and how variability in expression, either genetically or environmentally controlled, may contribute to variability in drug response in the patient.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Becker CM, Oberoi RK, McFarren SJ, Muldoon DM, Pafundi DH, Pokorny JL, Brinkmann DH, Ohlfest JR, Sarkaria JN, Largaespada DA, Elmquist WF. Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. Neuro Oncol. 2015 Sep;17(9):1210-9.
Parrish KE, Sarkaria JN, Elmquist WF. Improving drug delivery to primary and metastatic brain tumors: strategies to overcome the blood-brain barrier. Clin Pharmacol Ther. 2015 Apr;97(4):336-46.
Pokorny JL, Calligaris D, Gupta SK, Iyekegbe DO Jr, Mueller D, Bakken KK, Carlson BL, Schroeder MA, Evans DL, Lou Z, Decker PA, Eckel-Passow JE, Pucci V, Ma B, Shumway SD, Elmquist WF, Agar NY, Sarkaria JN. The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma. Clin Cancer Res. 2015 Apr 15;21(8):1916-24.
Gummadi T, Zhang BY, Valpione S, Kim C, Kottschade LA, Mittapalli RK, Chiarion-Sileni V, Pigozzo J, Elmquist WF, Dudek AZ. Impact of BRAF mutation and BRAF inhibition on melanoma brain metastases. Melanoma Res. 2015 Feb;25(1):75-9.
Vaidhyanathan S, Mittapalli RK, Sarkaria JN, Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos. 2014 Aug;42(8):1292-300.
Oberoi RK, Mittapalli RK, Fisher J, Elmquist WF. Sunitinib LC-MS/MS Assay in Mouse Plasma and Brain Tissue: Application in CNS Distribution Studies.Chromatographia. 2013 Dec 1;76(23-24).
Oberoi RK, Mittapalli RK, Elmquist WF. Pharmacokinetic assessment of efflux transport in sunitinib distribution to the brain. J Pharmacol Exp Ther. 2013 Dec;347(3):755-64
Sane R, Agarwal S, Mittapalli RK, Elmquist WF. Saturable active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier leads to nonlinear distribution of elacridar to the central nervous system. J Pharmacol Exp Ther. 2013 Apr;345(1):111-24.
Sane R, Mittapalli RK, Elmquist WF. Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability. J Pharm Sci. 2013 Apr;102(4):1343-54.
Li L, Agarwal S, Elmquist WF. Brain efflux index to investigate the influence of active efflux on brain distribution of pemetrexed and methotrexate. Drug Metab Dispos. 2013 Mar;41(3):659-67.
Dudek AZ, Raza A, Chi M, Singhal M, Oberoi R, Mittapalli RK, Agarwal S, Elmquist WF. Brain metastases from renal cell carcinoma in the era of tyrosine kinase inhibitors. Clin Genitourin Cancer. 2013 Jun;11(2):155-60.
Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013 Mar;344(3):655-64.
Agarwal S, Manchanda P, Vogelbaum MA, Ohlfest JR, Elmquist WF. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos. 2013 Jan;41(1):33-9.
Agarwal S, Mittapalli RK, Zellmer DM, Gallardo JL, Donelson R, Seiler C, Decker SA, Santacruz KS, Pokorny JL, Sarkaria JN, Elmquist WF, Ohlfest JR. Active efflux of Dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly targeted agents. Mol Cancer Ther. 2012 Oct;11(10):2183-92.
Sane R, Agarwal S, Elmquist WF. Brain distribution and bioavailability of elacridar after different routes of administration in the mouse. Drug Metab Dispos. 2012 Aug;40(8):1612-9.
Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther. 2012 Jul;342(1):33-40.
Agarwal S, Uchida Y, Mittapalli RK, Sane R, Terasaki T, Elmquist WF. Quantitative proteomics of transporter expression in brain capillary endothelial cells isolated from P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and P-gp/Bcrp knockout mice. Drug Metab Dispos. 2012 Jun;40(6):1164-9.
Agarwal S, Elmquist WF. Insight into the cooperation of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier: a case study examining sorafenib efflux clearance. Mol Pharm. 2012 Mar 5;9(3):678-84.
Wang T, Agarwal S, Elmquist WF. Brain distribution of cediranib is limited by active efflux at the blood-brain barrier. J Pharmacol Exp Ther. 2012 May;341(2):386-95.
Wang T, Oberoi RK, Elmquist WF. Determination of cediranib in mouse plasma and brain tissue using high-performance liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Dec 15;879(32):3812-7.
Agarwal S, Hartz AM, Elmquist WF, Bauer B. Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up. Curr Pharm Des. 2011;17(26):2793-802.
Agarwal S, Sane R, Oberoi R, Ohlfest JR, Elmquist WF. Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med. 2011 May 13;13:e17.
Li L, Sham YY, Bikadi Z, Elmquist WF. pH-Dependent transport of pemetrexed by breast cancer resistance protein. Drug Metab Dispos. 2011 Sep;39(9):1478-85. Epub 2011 May 31.
Winter TN, Elmquist WF, Fairbanks CA. OCT2 and MATE1 provide bidirectional agmatine transport. Mol Pharm. 2011 Feb 7;8(1):133-42.
Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther. 2011 Jan;336(1):223-33.
Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther. 2010 Jul;334(1):147-55.
Pan G, Winter TN, Roberts JC, Fairbanks CA, Elmquist WF. Organic cation uptake is enhanced in bcrp1-transfected MDCKII cells. Mol Pharm. 2010 Feb 1;7(1):138-45.
Chen Y, Agarwal S, Shaik NM, Chen C, Yang Z, Elmquist WF. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib. J Pharmacol Exp Ther. 2009 Sep;330(3):956-63.
Shaik N, Giri N, Elmquist WF. Investigation of the micellar effect of pluronic P85 on P-glycoprotein inhibition: cell accumulation and equilibrium dialysis studies. J Pharm Sci. 2009 Nov;98(11):4170-90.