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pharmacokinetics, brain, plasma

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https://www.readbyqxmd.com/read/27864744/a-generic-multi-compartmental-cns-distribution-model-structure-for-9-drugs-allows-prediction-of-human-brain-target-site-concentrations
#1
Yumi Yamamoto, Pyry A Välitalo, Dirk-Jan van den Berg, Robin Hartman, Willem van den Brink, Yin Cheong Wong, Dymphy R Huntjens, Johannes H Proost, An Vermeulen, Walter Krauwinkel, Suruchi Bakshi, Vincent Aranzana-Climent, Sandrine Marchand, Claire Dahyot-Fizelier, William Couet, Meindert Danhof, Johan G C van Hasselt, Elizabeth C M de Lange
PURPOSE: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition. METHODS: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments...
November 18, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/27845049/a-novel-role-for-pht1-in-the-disposition-of-l-histidine-in-brain-in-vitro-slice-and-in-vivo-pharmacokinetic-studies-in-wildtype-and-pht1-null-mice
#2
Xiao-Xing Wang, Yongjun Hu, Richard F Keep, Noriko Toyama-Sorimachi, David E Smith
PHT1 (SLC15A4) is responsible for translocating L-histidine (L-His), di/tripeptides and peptide-like drugs across biological membranes. Previous studies have indicated that PHT1 is located in brain parenchyma, however, its role and significance in brain along with effect on the biodistribution of substrates is unknown. In this study, adult gender-matched Pht1-competent (wildtype) and Pht1-deficient (null) mice were used to investigate the effect of PHT1 on L-His brain disposition via in vitro slice and in vivo pharmacokinetic approaches...
November 11, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27836941/target-site-investigation-for-the-plasma-prolactin-response-mechanism-based-pharmacokinetic-pharmacodynamic-analysis-of-risperidone-and-paliperidone-in-the-rat
#3
Shinji Shimizu, Sandra M den Hoedt, Victor Mangas Sanjuan, Sinziana Cristea, Jana K Geuer, Dirk-Jan van den Berg, Robin Hartman, Francisco Bellanti, Elizabeth C M de Lange
In order to understand the drivers in the biological system response to dopamine D2 receptor antagonists, a mechanistic semi-physiologically-based (PB) pharmacokinetic-pharmacodymanic (PKPD) model was developed to describe prolactin responses to risperidone (RIS) and its active metabolite paliperidone (PAL). A microdialysis study in rats was performed to obtain detailed plasma, brain extracellular fluid (brainECF), and cerebrospinal fluid (CSF) concentrations of PAL and RIS. To assess the impact of P-gp functioning on brain distribution, experiments were performed in absence or presence of the P-glycoprotein (P-gp) inhibitor tariquidar (TQD)...
November 11, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27830575/neuropharmacology-of-3-4-methylenedioxypyrovalerone-mdpv-its-metabolites-and-related-analogs
#4
Michael H Baumann, Mohammad O Bukhari, Kurt R Lehner, Sebastien Anizan, Kenner C Rice, Marta Concheiro, Marilyn A Huestis
3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects...
November 10, 2016: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/27810560/intranasal-delivery-of-ciprofloxacin-to-rats-a-topical-approach-using-a-thermoreversible-in-situ-gel
#5
Joana Sousa, Gilberto Alves, Paula Oliveira, Ana Fortuna, Amílcar Falcão
Intranasal administration of antibiotics is an alternative and attractive delivery approach in the treatment of local infections such as chronic rhinosinusitis. This topical route has the advantage of delivering high drug concentrations directly to the site of infection when trying to eradicate the highly resistant bacterial biofilms. The purpose of this study was to assess and compare the pharmacokinetic parameters of ciprofloxacin following intranasal and intravenous administrations to rats in plasma, olfactory bulb and nasal mucosa of two different nasal regions...
November 1, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27803466/comparative-physicochemical-and-pharmacokinetic-properties-of-quetiapine-and-its-active-metabolite-norquetiapine
#6
Dong-Wook Kim, Kwon-Yeon Weon, Eon-Pyo Hong, Eun Kyoung Chung, Kyung-Tae Lee
Quetiapine (QTP) is an atypical antipsychotic drug commonly used to treat several psychiatric disorders and is metabolized into the active metabolite norquetiapine (NQTP). This study was designed to evaluate and compare the physicochemical properties, metabolic stability, brain distribution, and pharmacokinetics of QTP and NQTP. Compared to QTP, NQTP had a higher pKa, solubility, and rat liver microsomal stability, optimal log D and similar log P values. For pharmacokinetic evaluation, QTP and NQTP were administered orally and intravenously to rats at various doses...
2016: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27799216/efavirenz-is-predicted-to-accumulate-in-brain-tissue-an-in-silico-in-vitro-and-in-vivo-investigation
#7
Paul Curley, Rajith K R Rajoli, Darren M Moss, Neill J Liptrott, Scott Letendre, Andrew Owen, Marco Siccardi
INTRODUCTION: Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to supress viral replication but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate efavirenz distribution into the cerebrospinal fluid (CSF) and brain using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. METHODS: Efavirenz CNS distribution was calculated using a permeability-limited model in a virtual cohort of 100 patients receiving efavirenz (600 mg once-daily)...
October 31, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27785749/revealing-the-neuroendocrine-response-after-remoxipride-treatment-using-multi-biomarker-discovery-and-quantifying-it-by-pk-pd-modeling
#8
Willem J van den Brink, Yin C Wong, Berfin Gülave, Piet H van der Graaf, Elizatbeth C M de Lange
To reveal unknown and potentially important mechanisms of drug action, multi-biomarker discovery approaches are increasingly used. Time-course relationships between drug action and multi-biomarker profiles, however, are typically missing, while such relationships will provide increased insight in the underlying body processes. The aim of this study was to investigate the effect of the dopamine D2 antagonist remoxipride on the neuroendocrine system. Different doses of remoxipride (0, 0.7, 5.2, or 14 mg/kg) were administered to rats by intravenous infusion...
October 26, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27775094/pharmacokinetic-comparison-between-quercetin-and-quercetin-3-o-%C3%AE-glucuronide-in-rats-by-uhplc-ms-ms
#9
Le-Le Yang, Na Xiao, Xiao-Wei Li, Yong Fan, Raphael N Alolga, Xiao-Yue Sun, Shi-Lei Wang, Ping Li, Lian-Wen Qi
Quercetin is a natural flavonoid widely distributed in human diet and functional foods. Quercetin 3-O-β-glucuronide (Q3G) is present in wine and some medicinal plants. Quercetin and Q3G may be metabolized from each other in vivo. While quercetin has been the subject of many studies, the pharmacokinetic profiles of quercetin and Q3G (in animals) have not yet been compared. Herein, we prepared a column-based method for rapid isolation of Q3G from Nelumbo nucifera. Then, we developed an UHPLC-MS/MS method to compare the pharmacokinetics of quercetin and Q3G...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27773722/prediction-of-pharmacokinetic-and-toxicological-parameters-of-a-4-phenylcoumarin-isolated-from-geopropolis-in-silico-and-in-vitro-approaches
#10
Marcos Guilherme da Cunha, Gilson César Nobre Franco, Marcelo Franchin, John A Beutler, Severino Matias de Alencar, Masaharu Ikegaki, Pedro Luiz Rosalen
In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array...
October 20, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27771379/novel-highly-potent-and-in%C3%A2-vivo-active-inhibitor-of-gaba-transporter-subtype-1-with-anticonvulsant-anxiolytic-antidepressant-and-antinociceptive-properties
#11
Kinga Sałat, Adrian Podkowa, Natalia Malikowska, Felix Kern, Jörg Pabel, Ewelina Wojcieszak, Katarzyna Kulig, Klaus T Wanner, Beata Strach, Elżbieta Wyska
BACKGROUND AND PURPOSE: Since GABAergic dysfunction underlies a variety of neurological and psychiatric disorders, numerous strategies leading to the augmentation of GABAergic neurotransmission have been introduced. One of them is the inhibition of GABA reuptake from the synaptic cleft mediated by four plasma membrane GABA transporters (GAT1-4). GAT1 which is exclusively expressed in the brain is an interesting target for centrally acting drugs. In this research, pharmacological properties of a novel, highly potent and selective inhibitor of GAT1, the guvacine derivative named DDPM-2571, were assessed in vivo...
October 19, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27764759/6-methoxyflavanone-attenuates-mechanical-allodynia-and-vulvodynia-in-the-streptozotocin-induced-diabetic-neuropathic-pain
#12
Shehla Akbar, Fazal Subhan, Nasiara Karim, Muhammad Shahid, Nisar Ahmad, Gowhar Ali, Wajahat Mahmood, Khwaja Fawad
BACKGROUND: Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities. OBJECTIVE: Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABAA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain...
October 17, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27755221/dihydroxyphenylglycol-as-a-biomarker-of-norepinephrine-transporter-inhibition-by-atomoxetine-human-model-to-assess-central-and-peripheral-effects-of-dosing
#13
Peter R Bieck, Mark Leibowitz, D Richard Lachno, Edouard Ledent, Robert Padich, Stan Jhee
To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system...
October 15, 2016: Journal of Clinical Psychopharmacology
https://www.readbyqxmd.com/read/27745731/prediction-of-cns-occupancy-of-dopamine-d2-receptor-based-on-systemic-exposure-and-in%C3%A2-vitro-experiments
#14
Kayoko Kanamitsu, Ryosuke Arakawa, Yuichi Sugiyama, Tetsuya Suhara, Hiroyuki Kusuhara
The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in humans. The occupancy of the dopamine D2 receptor and the plasma concentrations of the antipsychotic drugs quetiapine and perospirone in humans were collected from the literature or produced experimentally...
July 30, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27740776/oral-delivery-of-a-nanocrystal-formulation-of-schisantherin-a-with-improved-bioavailability-and-brain-delivery-for-the-treatment-of-parkinson-s-disease
#15
Tongkai Chen, Chuwen Li, Ye Li, Yi Xiang, Simon Ming Yuen Lee, Ying Zheng
Schisantherin A (SA) is a promising anti-Parkinsonism Chinese herbal medicine but with poor water solubility and challenges to be delivered to the brain. We formulated SA as nanocrystals (SA-NC), aiming to improve its solubility, pharmacokinetic profile and thus provide a potential therapeutic agent for the treatment of Parkinson's disease (PD). The rod-shaped SA-NC had a particle size of ~160 nm with 33.3% drug loading, and the nanocrystals exhibited a fast dissolution rate in vitro. The intact drug nanocrystals could be internalized into Madin-Darby canine kidney (MDCK) cells, which were followed by rapid intracellular release, and most of the drug was transported to the basolateral side in its soluble form...
October 14, 2016: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27731639/radiofluorinated-n-octanoyl-dopamine-18-f-f-nod-as-tool-to-study-tissue-distribution-and-elimination-of-nod-in-vitro-and-in-vivo
#16
Marc Pretze, Prama Pallavi, Mareike Roscher, Sarah Klotz, Julio Caballero, Uta Binzen, Wolfgang Greffrath, Rolf-Detlef Treede, Martin C Harmsen, Mathias Hafner, Benito Yard, Carmen Wängler, Björn Wängler
To mitigate pre-transplantation injury in organs of potential donors N-octanoyl dopamine (NOD) treatment might be considered as it does not affect hemodynamic parameters in brain dead (BD) donors. To better assess optimal NOD concentrations for donor treatment, we report on the fast and facile radiofluorination of the NOD-derivative [(18)F]F-NOD [(18)F]5 for in vivo assessment of NOD's elimination kinetics by means of PET imaging. [(18)F]5 was synthesized with reproducible high radiochemical yield and purity (>98%) as well as high specific activities (>20 GBq/µmol)...
October 12, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27725936/evaluation-of-neuroprotective-effect-of-thymoquinone-nanoformulation-in-the-rodent-cerebral-ischemia-reperfusion-model
#17
Xiao-Yu Xiao, Ying-Xian Zhu, Ju-Yuan Bu, Guo-Wei Li, Jian-Hui Zhou, Shao-Peng Zhou
The purpose of the present study was to evaluate the neuroprotective efficacy of optimized thymoquinone loaded PLGA-chitosan nanoparticles delivered via nose to brain route in the rodent cerebral ischemia-reperfusion model. The neuroprotective efficacy of the optimized thymoquinone loaded PLGA-chitosan nanoparticles was evaluated in middle cerebral artery occluded rats by various pharmacodynamic and biochemical studies. The pharmacokinetics of thymoquinone loaded PLGA-chitosan nanoparticles in the brain and blood plasma together with qualitative localization of florescent labelled PLGA-chitosan nanoparticles in brain tissues were also determined...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27718143/concentration-of-donepezil-in-the-cerebrospinal-fluid-of-ad-patients-evaluation-of-dosage-sufficiency-in-standard-treatment-strategy
#18
Martin Valis, Jiri Masopust, Oldrich Vysata, Jakub Hort, Rafael Dolezal, Jiri Tomek, Jan Misik, Kamil Kuca, Jana Zdarova Karasova
Although some studies have described the pharmacokinetics and pharmacodynamics of donepezil in the peripheral compartment, studies focused on drug transport across the blood-brain barrier are still very rare. To our knowledge, the fluctuation in the cerebrospinal fluid concentration of donepezil after administration of the drug has not been described in the literature so far. We recruited 16 patients regularly taking a standard therapeutic dose of donepezil (10 mg per day). All patients (Caucasian race) were treated for at least three months with a stable dose of 10 mg per day prior to sample collection...
October 7, 2016: Neurotoxicity Research
https://www.readbyqxmd.com/read/27700049/pharmacodynamic-relationships-between-duration-of-action-of-jdtic-like-kappa-opioid-receptor-antagonists-and-their-brain-and-plasma-pharmacokinetics-in-rats
#19
S Michael Owens, Gerald T Pollard, James L Howard, Timothy R Fennell, Rodney W Snyder, F Ivy Carroll
JDTic is a potent and selective κ-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [(35)S]GTPγS binding assay...
October 4, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27697728/an-easy-to-use-liquid-chromatography-assay-for-the-analysis-of-lamotrigine-in-rat-plasma-and-brain-samples-using-microextraction-by-packed-sorbent-application-to-a-pharmacokinetic-study
#20
Sandra Ventura, Márcio Rodrigues, Sarah Pousinho, Amílcar Falcão, Gilberto Alves
A simple and rapid high-performance liquid chromatography method with diode-array detection (HPLC-DAD) using microextraction by packed sorbent (MEPS) during the sample preparation step was developed and validated to quantify lamotrigine (LTG) in rat plasma and brain samples. MEPS variables such as pH, number of draw-eject cycles, and washing and desorption conditions were optimized. The chromatographic resolution of LTG and chloramphenicol, used as internal standard (IS), was accomplished in less than 5min on a C18 column, at 35°C, using an isocratic elution with acetonitrile (13%), methanol (13%) and water-triethylamine (99...
November 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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