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pharmacokinetics, brain, plasma

Wilhelmus E A de Witte, Vivi Rottschäfer, Meindert Danhof, Piet H van der Graaf, Lambertus A Peletier, Elizabeth C M de Lange
Drug-target binding kinetics (as determined by association and dissociation rate constants, k on and k off ) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug-target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment-target binding kinetics (EC-TB) model were tested on either plasma (ECPL , TBPL and EC-TBPL ) or brain extracellular fluid (ECF) (ECECF , TBECF and EC-TBECF ) morphine concentrations and EEG amplitude in rats...
May 18, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Yuki Yamasaki, Kaoru Kobayashi, Fuka Okuya, Naoyo Kajitani, Kanako Kazuki, Satoshi Abe, Shoko Takehara, Shingo Ito, Seiryo Ogata, Tatsuki Uemura, Sumio Ohtsuki, Genki Minegishi, Hidetaka Akita, Kan Chiba, Mitsuo Oshimura, Yasuhiro Kazuki
P-glycoprotein (P-gp), encoded by the MDR1 gene in humans and by the Mdr1a/1b genes in rodents, is expressed in numerous tissues and plays as an efflux pump to limit the distribution and absorption of many drugs. Owing to species differences of P-gp between humans and rodents, it is difficult to predict the impact of P-gp on pharmacokinetics and tissue distribution of P-gp substrates in humans from results of animal experiments. Therefore, we generated a novel P-gp humanized mouse model by using a mouse artificial chromosome (MAC) vector [designated human MDR1-MAC (hMDR1-MAC) mice]...
May 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jitka Široká, Martina Čečková, Lubor Urbánek, Vladimír Kryštof, Tomáš Gucký, Jakub Hofman, Miroslav Strnad, František Štaud
N2 -(4-Amino-cyclohexyl)-9-cyclopentyl-N6 -(6-furan-2-yl-pyridine-3-ylmethyl)-9H-purine-2,6-diamine (BP-14) and 2-(5-{[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purine-6-ylamino]-methyl}-pyridine-2-yl)-phenol (BP-20) are novel cyclin-dependent kinase inhibitors, structurally related to roscovitine, with significant biological activity. A simple, selective and sensitive liquid chromatography - tandem mass spectrometry method for determining them in rat plasma, using roscovitine as an internal standard, was developed and validated...
May 1, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Ningning Di, Wenna Cheng, Xingyue Jiang, Xinjiang Liu, Jinliang Zhou, Qian Xie, Zhihui Chu, Huacheng Chen, Bin Wang
PURPOSE: To investigate whether pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to evaluate vascular endothelial growth factor (VEGF) expression in brain glioma based on a point-to-point basis. MATERIALS AND METHODS: Forty-seven patients with treatment-naïve glioma received preoperative DCE-MRI before stereotactic biopsy. We histologically quantified VEGF from section of stereotactic biopsies, and co-registered biopsy locations with localized measurements of DCE-MRI parameters including volume transfer coefficient (Ktrans ), reverse reflux rate constant (Kep), extracellular extravascular volume fraction (Ve) and blood plasma volume (Vp)...
May 9, 2018: Journal of Neuroradiology. Journal de Neuroradiologie
Maximilian Kleinert, Petra Kotzbeck, Thomas Altendorfer-Kroath, Thomas Birngruber, Matthias H Tschöp, Christoffer Clemmensen
OBJECTIVE: The inability of leptin to suppress food intake in diet-induced obesity, sometimes referred to as leptin resistance, is associated with several distinct pathological hallmarks. One prevailing theory is that impaired transport of leptin across the blood-brain barrier (BBB) represents a molecular mechanism that triggers this phenomenon. Recent evidence, however, has challenged this notion, suggesting that leptin BBB transport is acquired during leptin resistance. METHODS: To resolve this debate, we utilized a novel cerebral Open Flow Microperfusion (cOFM) method to examine leptin BBB transport in male C57BL/6J mice, fed a chow diet or high fat diet (HFD) for 20 days...
April 27, 2018: Molecular Metabolism
Wenlong Li, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Els Wagenaar, Jos H Beijnen, Alfred H Schinkel
Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains...
May 9, 2018: International Journal of Cancer. Journal International du Cancer
W Cai, Q Cai, N Xiong, Y Qin, L Lai, X Sun, Y Hu
PURPOSE: To assess the pharmacokinetic properties of mycophenolate mofetil (MMF) dispersible tablets and capsules by the enzyme multiplied immunoassay technique (EMIT) in Chinese kidney transplant recipients in the early post-transplantation phase and to develop the equations to predict mycophenolic acid (MPA) area under the 12-hour concentration-time curve (AUC0-12h ) using a limited sampling strategy (LSS). METHODS: Forty patients who underwent renal transplantation from brain-dead donors were randomly divided into dispersible tablets (Sai KE Ping; Hangzhou Zhongmei Huadong Pharma) and capsules (Cellcept; Roche Pharma, Why, NSW, Australia) groups, and treated with MMF combined with combination tacrolimus and prednisone as a basic immunosuppressive regimen...
May 4, 2018: Transplantation Proceedings
Siti Norhawani Harun, Syafinaz Amin Nordin, Siti Salwa Abd Gani, Ahmad Fuad Shamsuddin, Mahiran Basri, Hamidon Bin Basri
Background and aim: Drugs that are effective against diseases in the central nervous system and reach the brain via blood must pass through the blood-brain barrier (BBB), a unique interface that protects against potential harmful molecules. This presents a major challenge in neuro-drug delivery. This study attempts to fabricate the cefuroxime-loaded nanoemulsion (CLN) to increase drug penetration into the brain when parenterally administered. Methods: The nanoemulsions were formulated using a high-pressure homogenization technique and were characterized for their physicochemical properties...
2018: International Journal of Nanomedicine
Lihan Sun, Huajing Wu, Lianjie Ren, Jiaojiao Cong, Xiaohui Qin, Xingli Wang, Xinming Qi, Lifeng Kang, Junying Zhang, Chunyong Wu
A sensitive and specific liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitative analysis of 1,2:5,6-dianhydrogalactitol (DAG) in mouse plasma and tissues. Sodium diethyldithiocarbamate (DDTC) was used as the derivatization reagent to improve its LC-MS/MS behavior. Analytes were separated on a Welch Ultimate XB-CN column with a mobile phase consisting of acetonitrile and 0.1% formic acid solution (65:35). The MS analysis was conducted by positive electrospray ionization in multiple-reaction monitoring (MRM) mode...
April 13, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Jing Sun, Huixia Huo, Yuelin Song, Jiao Zheng, Yunfang Zhao, Wenzhe Huang, Yonghua Wang, Jingbo Zhu, Pengfei Tu, Jun Li
Although wide applications towards ischemic stroke in clinic, the therapeutic materials of Longxuetongluo Capsule (LTC) that is composed of total phenolic extract of Chinese dragon's blood, are still largely unclear. Exposure pattern characterization of those drug-derived components in vivo, notably in circulation system has been recommended as a viable approach to disclose the effective components of a given herbal medicine. Herein, we aimed to develop a robust method being capable of multi-component quantification in either rat plasma or tissues following oral administration of LTC, and to clarify the kinetic profiles of 11 primary drug-derived phenolic derivatives...
April 22, 2018: Journal of Pharmaceutical and Biomedical Analysis
Izabel Almeida Alves, Keli Jaqueline Staudt, Fernando Olinto Carreño, Graziela de Araujo Lock, Carolina de Miranda Silva, Stela Maris Kuze Rates, Teresa Dalla Costa, Bibiana Verlindo De Araujo
PURPOSE: The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats. METHOD: The infection was induced by the administration of 100 μL of inoculum (1.105  CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats...
April 27, 2018: Pharmaceutical Research
Cortney A Turner, David M Lyons, Christine L Buckmaster, Elyse L Aurbach, Stanley J Watson, Alan F Schatzberg, Huda Akil
Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression...
April 9, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Jong-Suep Baek, Jie Kai Tee, Yi Yun Pang, Ern Yu Tan, Kah Leong Lim, Han Kiat Ho, Say Chye Joachim Loo
Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations...
April 25, 2018: Neuromolecular Medicine
Xinyi Yuan, Fuhuan Fei, Huanmei Sun, Chaoni Xiao, Xinfeng Zhao, Yajun Zhang, Xiaohui Zheng
Background: Tanshinol borneol ester (DBZ) is a hybrid of danshensu (DSS) and borneol and has anti-ischemic activity in animals. However, its low water solubility and short half-life limit its clinical application. Methods: We prepared polyethylene glycol (PEG)-modified and DBZ-loaded nanostructured lipid carriers (DBZ-PEG-NLC) and DBZ-NLC, and examined their physical characteristics, such as particle size, zeta potential, entrapment efficiency and drug loading. The in vitro stability and pharmacokinetics in rats as well as antioxidant activity of DBZ-PEG-NLC and DBZ-NLC in a C57BL/6 mouse model of ischemia/reperfusion-related brain injury were investigated...
2018: International Journal of Nanomedicine
Junjun Wang, Xuejin Yu, Ling Zhang, Ling Wang, Zhihong Peng, Yong Chen
Curcumin (CUR) is the major active component of turmeric and plays an important role in the prevention and treatment of many chronic diseases such as respiratory, neurodegenerative disease and so on. In the present work, a rapid and simple LC-MS/MS method was developed to investigate the pharmacokinetics and tissue distribution of CUR and its metabolites in mice after intravenous administration of CUR (20 mg/kg). The results showed that the AUC0-∞ were 107.0 ± 18.3, 6.0 ± 1.2 and 12.0 ± 4.0 (mg/L)·min, and the t1/2z were 32...
April 24, 2018: Biomedical Chromatography: BMC
P Gadgil, J Shah, D S-L Chow
The current study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) using design of experiment approach for enhancing lazaroid brain exposure. Response surface plots were used to determine the effects of independent variables (amount of PEGylating agent and liquid lipid) on dependent variables (particle size, zeta potential and encapsulation efficiency), while numerical optimization was used for optimizing LAZ-NLCs composition. The optimized LAZ-NLCs were spherical in shape with measured size of 172...
April 21, 2018: International Journal of Pharmaceutics
Philip Scheltens, Niels Prins, Adriaan Lammertsma, Maqsood Yaqub, Alida Gouw, Alle Meije Wink, Hui-May Chu, Bart N M van Berckel, John Alam
Objective: The aim of this study was to preliminarily evaluate an oral small molecule p38 α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic-pharmacodynamics correlations if any effects identified on these parameters. Methods: Sixteen patients with early AD received a highly selective p38 α inhibitor (neflamapimod) for 84 days (12 weeks)...
April 2018: Annals of Clinical and Translational Neurology
Yue Li, Man Li, Long Zuo, Qinglei Shi, Wei Qin, Lei Yang, Tao Jiang, Wenli Hu
Objective: Several studies have demonstrated that compromised blood-brain barrier (BBB) integrity may play a pivotal role in the pathogenesis of individual cerebral small vessel disease (cSVD) markers, but the association between BBB permeability and total magnetic resonance imaging (MRI) cSVD burden remains unclear. This study aimed to investigate the relationship between BBB permeability and total MRI cSVD burden. Methods: Consecutive participants without symptomatic stroke history presented for physical examination were enrolled in this cross-sectional study...
2018: Frontiers in Neurology
Rajalakshmi Rukmangathen, Indira Muzib Yallamalli, Prasanna Raju Yalavarthi
Selegiline hydrochloride, a hydrophilic anti-Parkinson' moiety, undergoes extensive first-pass metabolism and has low bioavailability. A process to obtain of selegiline (SH) loaded chitosan nanoparticles was attempted to circumvent the above problem, through intranasal delivery. SH loaded polymeric nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate, and stabilized by tween 80/ poloxamer 188. The resulting nanoparticles (NPs) were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, entrapment efficiency, particle size, zeta potential and surface morphology by scanning electron microscopy...
April 18, 2018: Current Drug Discovery Technologies
Niyaz Ahmad, Rizwan Ahmad, Md Aftab Alam, Farhan Jalees Ahmad
OBJECTIVE: To enhance brain bioavailability for intranasally administered Eugenol-encapsulated-chitosan-coated-PCL-Nanoparticles (CS-EUG-PCL-NPs). METHODS: Chitosan-coated-PCL-Nanoparticles (CS-PCL-NPs) were developed through double emulsification-solvent evaporation technique and further characterized for particle size, zeta potential, size distribution, encapsulation efficiency as well as in vitro drug release. UPLC-PDA method was developed to evaluate brain-drug uptake for optimized CS-EUG-PCL-NPs and to determine it's pharmacokinetic in rat's brain as well as plasma...
April 18, 2018: Drug Research
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