Advances in PET Imaging of P-Glycoprotein Function at the Blood-Brain Barrier
Department of Public Health and Caring Sciences, Uppsala University , Rudbecklaboratoriet, 751 85 Uppsala, Sweden.ACS Chemical Neuroscience (Impact Factor: 4.36). 02/2013; 4(2):225-37. DOI: 10.1021/cn3001729
Efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance observed in patient groups with refractory epilepsy and HIV. Altered P-gp function has also been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Positron emission tomography (PET), a molecular imaging modality, has become a promising method to study the role of P-gp at the BBB. The first PET study of P-gp function was conducted in 1998, and during the past 15 years two main categories of P-gp PET tracers have been investigated: tracers that are substrates of P-gp efflux and tracers that are inhibitors of P-gp function. PET, as a noninvasive imaging technique, allows translational research. Examples of this are preclinical investigations of P-gp function before and after administering P-gp modulating drugs, investigations in various animal and disease models, and clinical investigations regarding disease and aging. The objective of the present review is to give an overview of available PET radiotracers for studies of P-gp and to discuss how such studies can be designed. Further, the review summarizes results from PET studies of P-gp function in different central nervous system disorders.
- [Show abstract] [Hide abstract]
ABSTRACT: The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier.Pharmaceutical Research 06/2013; 30(11). DOI:10.1007/s11095-013-1119-z · 3.42 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar. Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar. [(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment. We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.Nuclear Medicine and Biology 07/2013; 40(6). DOI:10.1016/j.nucmedbio.2013.05.008 · 2.41 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The membrane-associated drug transporter, P-glycoprotein (P-gp), plays an essential role in drug efflux from the brain. Induction of this protein at the blood-brain barrier (BBB) could further affect drug permeability into the brain. At present, P-gp induction at the BBB mediated by antiretroviral drugs has not been fully investigated. Since P-gp expression is regulated by ligand-activated nuclear receptors i.e., human Pregnane X Receptor (hPXR) and human Constitutive Androstane Receptor (hCAR), these receptors could represent potential pathways involved in P-gp induction by antiretroviral drugs. The aims of this study were: i) to determine whether antiretroviral drugs currently used in HIV pharmacotherapy are ligands for hPXR or hCAR and ii) to examine P-gp function and expression in human brain microvessel endothelial cells treated with antiretroviral drugs identified as ligands of hPXR and/or hCAR. Luciferase reporter gene assays were performed to examine the activation of hPXR and hCAR by antiretroviral drugs. The hCMEC/D3 cell line, known to display several morphological and biochemical properties of the BBB in humans, was utilized to examine P-gp induction following 72 h exposure to these agents. Amprenavir, atazanavir, darunavir, efavirenz, ritonavir and lopinavir were found to activate hPXR, whereas, abacavir, efavirenz and nevirapine were found to activate hCAR. P-gp expression and function were significantly induced in hCMEC/D3 cells treated with these drugs at clinical plasma concentrations. Together, our data suggest that P-gp induction could occur at the BBB during chronic treatment with antiretroviral drugs identified to be ligands of hPXR and/or hCAR.Antimicrobial Agents and Chemotherapy 07/2013; 57(9). DOI:10.1128/AAC.00486-13 · 4.48 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.