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.)
- Laramy JK, Kim M, Parrish KE, Sarkaria JN, Elmquist WF. Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier. J Pharmacol Exp Ther. 2018 May;365(2):249-261. PMID: 29440450
- Gampa G, Kim M, Cook-Rostie N, Laramy J, Sarkaria JN, Paradiso L, DePalatis L, Elmquist WF. Brain distribution of a novel MEK inhibitor E6201: implications in the treatment of melanoma brain metastases. Drug Metab Dispos. 2018 Feb 2;. PMID: 29437873 [
- Kizilbash SH, Gupta SK, Chang K, Kawashima R, Parrish KE, Carlson BL, Bakken KK, Mladek AC, Schroeder MA, Decker PA, Kitange GJ, Shen Y, Feng Y, Protter AA, Elmquist WF, Sarkaria JN. Restricted delivery of talazoparib across the blood-brain barrier limits the sensitizing effects of PARP inhibition on temozolomide therapy in glioblastoma. Mol Cancer Ther. 2017;16:2735-2746.
- Laramy JK, Kim M, Gupta SK, Parrish KE, Zhang S, Bakken KK, Carlson BL, Mladek AC, Ma DJ, Sarkaria JN, Elmquist WF. Heterogeneous binding and central nervous system distribution of the multitargeted kinase inhibitor ponatinib restrict orthotopic efficacy in a patient-derived xenograft model of glioblastoma. J Pharmacol Exp Ther. 2017;363(2):136-147.
- Sarkaria JN, Hu LS, Parney IF, Pafundi DH, Brinkmann DH, Laack NN, Giannini C, Burns TC, Kizilbash SH, Laramy JK, Swanson KR, Kaufmann TJ, Brown PD, Agar NYR, Galanis E, Buckner JC, Elmquist WF. Is the blood-brain barrier really disrupted in all glioblastomas? - A critical assessment of existing clinical data. Neuro Oncol. 2017 Sep 7. doi: 10.1093/neuonc/nox175.
- Gampa G, Vaidhyanathan S, Sarkaria JN, Elmquist WF. Drug delivery to melanoma brain metastases: Can current challenges lead to new opportunities? Pharmacol Res. 2017 Sep;123:10-25.
- Gampa G, Vaidhyanathan S, Resman BW, Parrish KE, Markovic SN, Sarkaria JN, Elmquist WF. Challenges in the delivery of therapies to melanoma brain metastases. Curr Pharmacol Rep. 2016;2(6):309-325.
- Mittapalli RK, Chung AH, Parrish KE, Crabtree D, Halvorson KG, Hu G, Elmquist WF, Becher OJ. ABCG2 and ABCB1 limit the efficacy of dasatinib in a PDGF-B-driven brainstem glioma model. Mol Cancer Ther. 2016;15(5):819-29.
- Vaidhyanathan S, Wilken-Resman B, Ma DJ, Parrish KE, Mittapalli RK, Carlson BL, Sarkaria JN, Elmquist WF. Factors influencing the central nervous system distribution of a novel phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor GSK2126458: Implications for overcoming resistance with combination therapy for melanoma brain metastases. J Pharmacol Exp Ther. 2016;356(2):251-9.
- Oberoi RK, Parrish KE, Sio TT, Mittapalli RK, Elmquist WF, Sarkaria JN. Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro Oncol. 2016;18:27-36.
- 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;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;97(4):336-346.
- 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;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;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;42:1292-300.
- 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;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;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;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;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;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;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;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;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;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;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;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;40:1164-9.
- 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;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;341(2):386-95.