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Vivo Pharmacokinetics (vivo + pharmacokinetic)
Terms modified by Vivo Pharmacokinetics Selected AbstractsUse of 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl as an EPR oximetry probe: Potential for in vivo measurement of tissue oxygenation in mouse brainMAGNETIC RESONANCE IN MEDICINE, Issue 6 2006Jiangang Shen Abstract Measurement of oxygen concentration and distribution in the brain is essential for understanding the pathophysiology of stroke. Low-frequency electron paramagnetic resonance (EPR) spectroscopy with a paramagnetic probe is an attractive imaging modality that potentially can be used to map O2 concentration in the brain. We examined two nitroxides, 3-methoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl [2] and 3-acetoxymethoxycarbonyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl [3], as pro-imaging agents to deliver 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl [1] across the blood,brain barrier (BBB). In primary cultured neurons, nitroxide [3] but not [2] was hydrolyzed by intracellular esterases to [1], which, being anionic at physiologic pH, was well retained intracellularly. In contrast, [2] was not well retained by neurons. In vivo pharmacokinetic and pharmacodynamic studies in mice suggested that esterase-labile nitroxide [3] crossed the BBB, and was converted to [1] and retained. Retention occurred in brain tissue and not in the extensive vasculature, as evidenced by the fact that removal of blood by whole-body saline perfusion did not eliminate the nitroxide EPR signal from the brain. The EPR linewidths of [1] and [3] were more O2 -sensitive than that of the commonly-used oximetry probe 4-oxo-2,2,6,6-tetramethylpiperidine-d16 -1- 15N-oxyl [4]. Moreover, we used [3] in vivo to estimate O2 concentration in mouse brains. These results indicate that nitroxide [3] could be useful for mapping O2 distribution in the brain following stroke. Magn Reson Med, 2006. © 2006 Wiley-Liss, Inc. [source] High-throughput analysis in drug discovery: application of liquid chromatography/ion-trap mass spectrometry for simultaneous cassette analysis of ,-1a antagonists and their metabolites in mouse plasmaRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 8 2001Zongwei Cai The application of liquid chromatography/ion-trap mass spectrometry for simultaneous quantification of multiple drugs and detection of their metabolites for in vitro experiments was reported recently. In the current study, the use of these techniques was extended to in vivo pharmacokinetic (PK) studies of ,-1a antagonists. In combination with limited time-point PK, greatly increased throughput was demonstrated for the in vivo screening and investigation of in vivo,in vitro correlation. In addition to quantitative analyses, the technique allowed simultaneous detection of major in vivo metabolites without having to reanalyze the plasma samples. The drugs were individually dosed in mice intravenously via tail vein injection and the blood samples were collected 5,min and 2,h after dosing. After the plasma samples for the different drugs had been prepared separately, they were pooled for cassette analysis. The concentrations of five test compounds in the plasma samples at 2,h ranged from 36,1062,ng/mL, whereas their 5-min plasma levels were similar. From the same cassette analysis, major metabolites in the samples were also detected simultaneously through the interpretation of full-scan mass spectra. The metabolite identification confirmed the results from a previous report that the major sites of metabolism are hydroxylation of the phenyl ring not bearing the alkylsulfonamide substitutent, piperidine N-dealkylation, and N-demethylation of the alkylsulfonamide group. Copyright © 2001 John Wiley & Sons, Ltd. [source] Characterization of pegylated copolymeric micelles and in vivo pharmacokinetics and biodistribution studiesJOURNAL OF BIOMEDICAL MATERIALS RESEARCH, Issue 1 2006Wen-Jen Lin Abstract The aim of this study was to evaluate the influence of pegylated copolymeric micelle carrier on the biodistribution of drug in rats. The copolymers were synthesized via a modified ring-opening copolymerization of lactone monomers (,-caprolactone, ,-valerolactone, L -lactide) and poly(ethylene glycol) (PEG10,000 and PEG4000). The molecular weights and the polydispersities of synthesized copolymers were in the range of 15,000,31,000 g/mol and 1.7,2.7, respectively. All of the pegylated amphiphilic copolymers were micelles formed with low CMC values in the range of 10,7,10,8M. The drug-loaded micelles were prepared via a dialysis method. The average particle size of micelles was around 150,200 nm. The cytotoxicity in terms of cell viability after treated with PCL,PEG, PVL,PEG, and PLA,PEG micelles was insignificant. PCL,PEG and PVL,PEG micelles without branch side chain in structures had higher drug loading than PLA,PEG micelles. In vitro release profiles indicated the release of indomethacin from these micelles exhibited a sustained release behavior. The similar phenomenon was also observed in vivo in rats. The pegylated copolymeric micelles not only decreased drug uptake by the liver and kidney, but also prolonged drug retention in the blood. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006 [source] Fully automated high yield synthesis of (R)- and (S)-[11C]verapamil for measuring P-glycoprotein function with positron emission tomographyJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 14 2002Gert Luurtsema Abstract Racemic (±) verapamil is a well characterized substrate for P-glycoprotein (P-gp). However, the in vivo pharmacokinetics and pharmacodynamics of both enantiomers are reported to be different. In the preparation of evaluation studies of both enantiomers in animals and humans, the purpose of the present study was to optimize and automate the synthesis of (R)- and (S)-[11C]verapamil. (R)- and (S)-[11C]verapamil were prepared from (R)- and (S)-desmethyl-verapamil, respectively, by methylation with no-carrier added [11C]methyliodide or [11C]methyltriflate. Different conditions of the methylation reaction were studied: reaction time, temperature, base and solvent, and chemical form of the precursor using either the hydrochloric acid salt or the free base of the starting material. After optimization, the synthesis was fully automated using home-made modules and performed according to GMP guidelines. Optimal yields of 60,70% for the methylation reaction were obtained using 1.5 mg of the free base of (R)- or (S)-desmethyl-verapamil in 0.5 ml of acetonitrile at 50°C for 5 min with [11C]methyltriflate as methylating agent. Under the same reaction conditions, but with a reaction temperature of 100°C, the radiochemical yield starting with [11C]methyliodide as methylation reagent was 40%. The specific activity of (R)- and (S)-[11C]verapamil was >20 GBq/,mol and the radiochemical purity was >99% for both methods. The total synthesis time was 45 min. The automated high yield synthesis of (R)- and (S)-[11C]verapamil provides the means for evaluating both enantiomers as in vivo tracers of P-gp function. Copyright © 2002 John Wiley & Sons, Ltd. [source] In vivo pharmacokinetics of ketoprofen after patch application in the Mexican hairless pigBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2009Masafumi Horie Abstract To evaluate the pharmacokinetics of topical drugs, in vitro permeation studies are performed using sacrificed pig skin or human tissues resected at surgery; however, these methods have their limitations in in vivo pharmacokinetics. This study examined the usefulness of Mexican hairless pigs for in vivo pharmacokinetic study, especially the drug concentration in the tissues. A ketoprofen patch was applied on the back of Mexican hairless pigs for 24,h, followed by sequential collection of blood specimens from 0 to 36,h (n=3). Also, the skin, subcutaneous fat, fascia and muscle from the center of the site of application were excised at 12,h after the application (n=4). Ketoprofen was first detected in the plasma at 8,h, the concentration increasing up to 24,h; the plasma concentration began to decrease after the removal of the ketoprofen patch. Ketoprofen concentrations in the tissues decreased with increasing depth of the tissues, but the values in the deep muscles, being the lowest among the tissues examined, were still higher than those in the plasma. While the data of drug concentration in human tissue are difficult to test, the Mexican hairless pig model appears to be attractive for in vivo pharmacokinetic studies of topically applied ketoprofen. Copyright © 2009 John Wiley & Sons, Ltd. [source] | |||||||||||||