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Pharmaco kinetics , metabolism

Novera Alam, Mia G Angeli, David J Greenblatt
OBJECTIVES: The direct-acting protease inhibitor paritaprevir is a new pharmaco-logic option available for treatment of chronic hepatitis C (HCV). Paritaprevir is reported to inhibit human UGT 1A1, but the mechanism of inhibition and its possible clinical consequences are not established. Our objective was to evaluate the in-vitro metabolic interaction between paritaprevir and the oral contraceptive steroid ethinyl estradiol (EE), a UGT 1A1 substrate. METHODS: Enzyme kinetic parameters were determined using human liver microsomes for the biotransformation of EE to its glucuronide metabolites, and the potency and mechanism of inhibition by paritaprevir...
October 9, 2017: Journal of Pharmacy and Pharmacology
Monica Piras, Andrea Testa, Ian N Fleming, Sergio Dall'Angelo, Alexandra Andriu, Sergio Menta, Mattia Mori, Gavin D Brown, Duncan Forster, Kaye J Williams, Matteo Zanda
Nonpeptidic Arg-Gly-Asp (RGD)-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent in vitro properties (high αv β3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g., tritium and fluorine-18, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD mimics to αv β3 or αIIb β3 receptors was investigated by molecular modeling simulations...
July 20, 2017: ChemMedChem
R Pérez, C Palma, R Burgos, J A Jeldres, A Espinoza, A K Peñailillo
The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)-induced acute phase response (APR) on the pharmaco-kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 ± 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1...
April 2016: Journal of Veterinary Pharmacology and Therapeutics
Amanda Robinson, Daniel P Wermeling
PURPOSE: The pharmacology, pharmaco-kinetic properties, and clinical efficacy of naloxone injection administered intranasally for the reversal of opioid overdose are reviewed. SUMMARY: Naloxone is an opioid-receptor antagonist that is used in the treatment of opioid overdose to reverse the respiratory and central nervous system-depressant effects of the opioid. Naloxone injection is traditionally given by intravenous, intramuscular, and subcutaneous routes. Paramedics also administer naloxone injection intranasally in the prehospital setting to treat suspected opioid overdose...
December 15, 2014: American Journal of Health-system Pharmacy: AJHP
Maya Amitai, Sefi Kronenberg, Tali Cohen, Amos Frisch, Abraham Weizman, Alan Apter
Anxiety disorders are chronic disorders appearing with a high frequency in the general population and causing much distress to those suffering from them. The current common treatment consists of antidepressants, primarily from the serotonin-selective-reuptake-inhibitor (SSRI) class. However, despite the relative effectiveness of these medications the patients' responses vary widely with one third not responding at all. While we do not currently have the ability to predict who will respond positively to the medication, it is hoped that genetic research will make it possible to prospectively identify responders and thus help avoid failed treatment attempts and side-effects...
March 2014: Harefuah
Wolfgang Wiechert, Katharina Nöh, Michael Weitzel
Isotope labeling systems (ILSs) are sets of balance equations that quantitatively describe the distribution of isotopic tracers in metabolic networks. The solution of ILSs, i.e., the calculation of isotopic labeling distributions (mostly in steady state) is the fundamental computational step of (13)C metabolic flux analysis (MFA). Aiming at a deeper analytical understanding of ILSs a new approach for solving ILSs is developed. It is based on the straightforward idea of tracing labeled molecules through the metabolic network...
July 2013: Mathematical Biosciences
Falko Partosch, Hans Mielke, Ursula Gundert-Remy
Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood...
July 2013: Archives of Toxicology
Osama K Abou-Zied, Najla Al-Lawatia, Marcus Elstner, Thomas B Steinbrecher
Human serum albumin (HSA) is the most abundant protein in blood plasma. It has high relevance for the lipid metabolism, and its ability to bind a large variety of natural and pharmaceutical compounds makes it a crucial determinant of drug pharmaco-kinetics and -dynamics. The drug binding properties of HSA can be characterized by spectroscopic analysis of bound probe molecules. We have recently characterized the subdomain IIA binding site of HSA using three hydroxyquinoline derivatives. In this work, we extend our study by combining data from energy transfer experiments, ligand docking, and long molecular dynamics (MD) simulations...
January 31, 2013: Journal of Physical Chemistry. B
Jitesh D Kawedia, Chengcheng Liu, Deqing Pei, Cheng Cheng, Christian A Fernandez, Scott C Howard, Dario Campana, John C Panetta, W Paul Bowman, William E Evans, Ching-Hon Pui, Mary V Relling
We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti-asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors...
February 16, 2012: Blood
Sooyeun Lee, Eunyoung Han, Eunmi Kim, Hwakyung Choi, Heesun Chung, Seung Min Oh, Young Mi Yun, Seok Hun Jwa, Kyu Hyuck Chung
In forensic toxicology, the abuse of various opiate preparations, such as raw opium and heroin, is of interest since the metabolic pathways of these opiates overlap. Although the pharmaco(toxico)kinetics in hair is not clearly understood, melanin is thought to play a key part in the incorporation and distribution of drugs and metabolites in hair. Therefore, in the present study, a simultaneous quantification method for the determination of codeine, morphine, norcodeine, normorphine and 6-acetylmorphine (6-AM) in hair was developed in order to analytically diagnose chronic users of opiates including morphine and codeine preparations, raw opium and heroin...
November 2010: Archives of Pharmacal Research
Helen K Tomkinson, John V Kemp, Thomas Wollseifen, Thomas Morris, Stuart D Oliver
BACKGROUND: Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur...
July 2010: Clinical Therapeutics
David C Klonoff, Claudio Cobelli, Boris Kovatchev, Howard C Zisser
This issue of Journal of Diabetes Science and Technology contains a collection of 12 original articles describing the latest advances in the development of algorithms for controlling insulin delivery in an artificial pancreas. Algorithms presented in this issue are affected by numerous quantifiable factors, including insulin pharmaco-kinetics, timing of meal carbohydrate appearance, meal size, amount of exercise, presence of stress, day-to-day variations in insulin sensitivity, insulin time-activity profiles, accuracy of glucose monitor calibration, metabolic profiles of both adults and neonates, and risks of hypoglycemia/hyperglycemia...
September 1, 2009: Journal of Diabetes Science and Technology
E Sestigiani, M Mandreoli, M Guardigli, A Roda, E Ramazzotti, P Boni, A Santoro
AIMS: Hyperuricemia is a risk factor associated with cardiovascular and renal disease. Recently, rasburicase, a recombinant urate oxidase, has been developed for the treatment of hyperuricemia in patients with primarily hematological malignancies. We studied the pharmacokinetics and metabolism of rasburicase in the treatment of chronic asymptomatic hyperuricemia in chronic kidney disease (CKD) patients. MATERIALS AND METHODS: We studied 9 CKD patients with hyperuricemia, whose mean serum acid concentration was 10...
2008: Nephron. Clinical Practice
Todd Correll, Olga M Klibanov
The emergence of antiretroviral drug resistance in patients infected by the human immunodeficiency virus (HIV) has prompted efforts to develop new antiretrovirals that differ from existing agents with regard to mechanism of action and resistance profiles. We evaluated the literature regarding a new class of antiretrovirals, the integrase inhibitors. A MEDLINE search (January 1996-May 2007) was performed to identify relevant clinical trials and review articles; abstracts from HIV conferences were also searched...
January 2008: Pharmacotherapy
Yong-Mei Hu, Qiao Mei, Xin-Hua Xu, Xiang-Peng Hu, Nai-Zhong Hu, Jian-Ming Xu
AIM: To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups. METHODS: The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM)...
August 7, 2006: World Journal of Gastroenterology: WJG
S Carozzo, S Fornaro, S Garbarino, M Saturno, W G Sannita
A continuum from neuronal cellular/subcellular properties to system processes appears to exist in many instances and to allow privileged approaches in neuroscience and neuropharmacology research. Brain signals and the cholinergic and GABAergic systems, in vivo and in vitro evidence from studies on the retina, or the "gamma band" oscillations in neuron membrane potential/spiking rate and neuronal assemblies are examples in this respect. However, spontaneous and stimulus-event-related signals at any location and time point reflect brain state conditions that depend on neuromodulation, neurotransmitter interaction, hormones (e...
April 2006: Clinical EEG and Neuroscience: Official Journal of the EEG and Clinical Neuroscience Society (ENCS)
Peter Bendel
This review focuses mainly on the detection and investigation of molecules used for boron neutron capture therapy (BNCT) by 10B and 11B NMR. In this binary radiation treatment, boron-containing molecules (also called 'BNCT agents') enriched in the 10B isotope, are targeted to the tumor, and irradiated with thermal or epithermal neutrons. Capture of these neutrons by 10B nuclei generates cell-damaging radiation, confined to single cell dimensions. NMR research efforts have primarily been applied in two directions: first, to investigate the metabolism and pharmaco-kinetics of BNCT agents in-vivo, and second, to use localized NMR spectroscopy and/or MRI for non-invasive mapping of the administered molecules in treated animals or patients...
April 2005: NMR in Biomedicine
Adrian Leucuţa, Laurian Vlase, Dorin Farcau, Mircea Nanulescu
The pharmacokinetics of diclofenac sodium in healthy volunteers was evaluated to determine if previously repeated doses of ranitidine inhibited the metabolism of the non-steroidal anti-inflammatory drug. Diclofenac sodium 50 mg (tablets) in combination with ranitidine 150 mg (tablets) were administered to 14 healthy human volunteers in a two treatment study design, separated by 5 days in which the ranitidine alone was administrated in single p.o. doses twice daily. Plasma concentrations of diclofenac were determined during a 12 hour period following drug administration...
December 2004: Romanian Journal of Gastroenterology
Staffan Edsbäcker, Tommy Andersson
This overview summarises available pharmacokinetic data on budesonide capsules (Entocort EC), approved for the treatment of mild-to-moderate active Crohn's disease involving the ileum and/or ascending colon and for prolongation of symptom control. Budesonide is a locally-acting glucocorticosteroid with an extensive, primarily hepatic, metabolism after oral administration. It is rapidly absorbed and biotransformed by cytochrome P450 (CYP) 3A to metabolites with negligible glucocorticoid activity. Entocort EC, a pH- and time-dependent oral formulation of budesonide, was developed to optimise drug delivery to the ileum and throughout the colon...
2004: Clinical Pharmacokinetics
Hisataka Moriwaki, Yoshiyuki Miwa, Masahiro Tajika, Masahiko Kato, Hideki Fukushima, Makoto Shiraki
Protein-energy malnutrition (PEM) is a common manifestation in cirrhotic patients with reported incidences as high as 65-90%. PEM affects largely the patients' quality of life and survival. Thus, diagnosis of and intervention for PEM is important in the clinical management of liver cirrhosis. Supplementation with branched-chain amino acids (BCAA) is indicated to improve protein malnutrition. As an intervention for energy malnutrition, frequent meal or late evening snack has been recently recommended. Plasma amino acid analysis characterizes the patients with liver cirrhosis to have decreased BCAA...
January 9, 2004: Biochemical and Biophysical Research Communications
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