Abstract：
PURPOSE:To show, using a model study, how electronic structure theory can be applied in combination with LC/UV/MS/MS for the prediction and identification of oxidative degradants. METHODS:The benzyloxazole 1, was used to represent an active pharmaceutical ingredient for oxidative forced degradation studies. Bond dissociation energies (BDEs) calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level with isodesmic corrections were used to predict sites of autoxidation. In addition, frontier molecular orbital (FMO) theory at the Hartree-Fock level was used to predict sites of peroxide oxidation and electron transfer. Compound 1 was then subjected to autoxidation and H2O2 forced degradation as well as formal stability conditions. Samples were analyzed by LC/UV/MS/MS and degradation products proposed. RESULTS:The computational BDEs and FMO analysis of 1 was consistent with the LC/UV/MS/MS data and allowed for structural proposals, which were confirmed by LC/MS/NMR. The autoxidation conditions yielded a number of degradants not observed under peroxide degradation while formal stability conditions gave both peroxide and autoxidation degradants. CONCLUSIONS:Electronic structure methods were successfully applied in combination with LC/UV/MS/MS to predict degradation pathways and assist in spectral identification. The degradation and excipient stability studies highlight the importance of including both peroxide and autoxidation conditions in forced degradation studies.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Reid DL,Calvitt CJ,Zell MT,Miller KG,Kingsmill CAdoi
10.1023/b:pham.0000041469.96466.12subject
Has Abstractpub_date
2004-09-01 00:00:00pages
1708-17issue
9eissn
0724-8741issn
1573-904Xjournal_volume
21pub_type
杂志文章abstract：PURPOSE:Following extracellular drug clearance, we analyzed the rate of doxorubicin efflux from the nucleus of three human leukemic cells (K562, Molt4 and CCRF-CEM) and related it to their differential sensitivity to this drug, after a short drug pulse. RESULTS:For many pulse-chase regimes, K562 cell viability was lea...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-007-9369-2
更新日期：2007-11-01 00:00:00
abstract：PURPOSE:Labrasol and Gelucire 44/14 are defined admixtures of acylglycerols and PEG esters which are substrates for digestive lipases. METHODS:We investigated their in vitro gastrointestinal lipolysis to understand which compounds are, after digestion, responsible for keeping poorly water-soluble drugs in solution. Th...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-009-9906-2
更新日期：2009-08-01 00:00:00
abstract：PURPOSE:A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with contr...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-017-2205-4
更新日期：2017-10-01 00:00:00
abstract：PURPOSE:Permeation studies, with near infrared (NIR) light and anti-aggregation antibody formulation, were used to investigate the in vitro permeation of bevacizumab, ranibizumab and aflibercept through human sclera. METHODS:A vertical, spherical Franz cell diffusion apparatus was used for this scleral tissue permeati...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-018-2392-7
更新日期：2018-03-29 00:00:00
abstract：:Lidocaine was administered to healthy volunteers at different sites in the rectum. Unchanged drug and monoethylglycinexylidide (MEGX) concentrations were measured in plasma with a newly developed gas chromatographic method. Lidocaine was given rectally by means of an osmotic system (Osmet(®)) which delivered 25 mg/h a...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/A:1016380104424
更新日期：1984-05-01 00:00:00
abstract：PURPOSE:The purpose was to develop a population pharmacokinetic model for montelukast after intravenous administration. Clinical trial simulations were conducted using the model developed to identify the lowest intravenous dose in 6- to 14-year-old children that would give montelukast systemic exposures that were compa...
journal_title：Pharmaceutical research
pub_type： 杂志文章,随机对照试验
doi：10.1007/s11095-005-2493-y
更新日期：2005-04-01 00:00:00
abstract：:A physical-chemical analysis of the extent of sorption of water by tablets containing superdisintegrants was carried out following the aqueous film coating of formulated tablets. Characterization of the uncoated and coated tablet properties was conducted using thermogravimetric analysis, differential scanning calorime...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018932705370
更新日期：1993-08-01 00:00:00
abstract：PURPOSE:Evista (raloxifene HCl) is a nonsteroidal selective estrogen receptor modulator that displays estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium. The potential for drug-drug interaction between raloxifene and warfarin was assessed in 15 healthy po...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1010904815275
更新日期：2001-07-01 00:00:00
abstract：PURPOSE:This study seeks to develop fiber membranes for local sustained delivery of 25-hydroxyvitamin D3 to induce the expression and secretion of LL-37 at or near the surgical site, which provides a novel therapeutic approach to minimize the risk of infections. METHODS:25-hydroxyvitamin D3 loaded poly(L-lactide) (PLA...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-015-1667-5
更新日期：2015-09-01 00:00:00
abstract：:We describe a simplified and rapid liquid chromatographic determination of antipyrine clearance (CLAP) calculated from peak height ratios of drug/internal standard. Saliva or plasma was collected 24 hr after the oral administration of 1 g of antipyrine to the subject. A 25-microliter aliquot of the sample is deprotein...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015816825920
更新日期：1991-02-01 00:00:00
abstract：:A novel application of attenuated total reflectance IR spectroscopy (ATR-IR) was used to monitor the outer several microns of the stratum corneum (SC) and, thereby, demonstrate enhanced percutaneous absorption in vivo in man. 4-Cyanophenol (CP) as a model permeant yielded a unique IR signal, distinct from those of the...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015960815578
更新日期：1990-08-01 00:00:00
abstract：:A new high-performance liquid chromatographic (HPLC) assay suitable for pharmacokinetic studies of enantiomers of fenoprofen (FEN) was developed. Following the addition of internal standard (IS; racemic ketoprofen), the plasma or urine constituents are extracted into a mixture of isooctane:isopropanol (95:5), back ext...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015867513045
更新日期：1988-01-01 00:00:00
abstract：PURPOSE:The aim of the present study was to design a new mucosal drug delivery system composed of liposomes dispersed within a bioadhesive hydrogel containing methyl-beta-cyclodextrin (Me(beta)CD) for controlled drug release. METHODS:A hydrophilic model molecule, inulin, was encapsulated within positively charged and ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-005-4591-2
更新日期：2005-06-01 00:00:00
abstract：PURPOSE:The purpose of the present study was to use the human colorectal carcinoma cell line. Caco-2, as a human intestinal epithelial model for studying the effects of cyclodextrins as absorption enhancers. METHODS:Cyclodextrins of varying sizes and physicochemical characters were investigated. The effects of the cyc...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016225707807
更新日期：1995-09-01 00:00:00
abstract：PURPOSE:To characterize the uptake mechanism of zidovudine (AZT), a nucleoside reverse transcriptase inhibitor, in syncytiotrophoblast cells using the TR-TBT 18d-1 cell line previously established by our group. MATERIALS AND METHODS:The effects of several transporter inhibitors on the initial and steady-state apical u...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-008-9564-9
更新日期：2008-07-01 00:00:00
abstract：:5'-Ester derivatives of 5-iodo-2'-deoxyuridine (IDU) with varying degrees of lipophilicity were examined to evaluate the effectiveness of lipophilic ester prodrugs for enhanced and sustained delivery of IDU to the brain parenchyma. Approximately 1.0% (1.0 +/- 0.19; n = 4) of the total radioactivity was found in the br...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015803922401
更新日期：1992-09-01 00:00:00
abstract：PURPOSE:We aimed to assess the fate of β-arteether lipid-based drug delivery systems (AE-LBDDS) in terms of resistance to lipolysis and permeation across intestinal cells. METHODS:AE-LBDDS contained Tween 80 or Cremophor EL as surfactants, ethanol, Maisine 35-1 and vegetable oil. The solubilization behavior of AE was ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-013-1094-4
更新日期：2013-10-01 00:00:00
abstract：BACKGROUND:Little is known about the affinity and stability of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability. METHODS:99mTc-...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-018-2548-5
更新日期：2018-11-29 00:00:00
abstract：:The possible mechanism of hepatic uptake of colchicine (CLC), a microtubule system disrupting agent, was examined using isolated rat hepatocytes. The existence of a carrier-mediated active transport system for CLC was demonstrated. This transport system is saturable, is affected by metabolic inhibitors (dinitrophenol,...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015917601349
更新日期：1989-03-01 00:00:00
abstract：PURPOSE:To study the influence of crystallizing and non-crystallizing cosolutes on the crystallization behavior of trehalose in frozen solutions and to monitor the phase behavior of trehalose dihydrate and mannitol hemihydrate during drying. METHODS:Trehalose (a lyoprotectant) and mannitol (a bulking agent) are widely...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-010-0221-8
更新日期：2010-11-01 00:00:00
abstract：:The influence of varying protein and fat content in milk of New Zealand White rabbits on the milk-to-plasma drug concentration (M/P) ratio of diazepam was studied. At various time points after littering, a bolus dose (1.5 mg/kg) followed by a 26-hr infusion (1.8 mg/h) of diazepam was administered to freely moving rabb...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015809418284
更新日期：1992-10-01 00:00:00
abstract：PURPOSE:The blood-brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model. MATERIALS AND METHODS...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-014-1593-y
更新日期：2015-06-01 00:00:00
abstract：PURPOSE:To compare the permeation characteristics of amide bond-containing HIV-1 protease inhibitors and their pyrrolinone-containing counterparts across Caco-2 cell monolayers, a model of the intestinal mucosa. METHODS:Transepithelial transport and cellular uptake of three pairs of amide bond-containing and pyrrolino...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1011966918959
更新日期：1998-05-01 00:00:00
abstract：PURPOSE:To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes. METHODS:To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty ac...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-011-0542-2
更新日期：2012-01-01 00:00:00
abstract：PURPOSE:To describe a computational tool to calculate molecular descriptors of potential application in ADME virtual screening of antitumor Pt(II) drug candidates. METHODS:The multistep computational procedure consists in (a) building and optimization (PM3) of the 3D structures of the investigated complexes, (b) param...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-010-0317-1
更新日期：2011-03-01 00:00:00
abstract：:Physicochemical effects caused by intestinal fluids on drugs in the gastrointestinal (GI) tract can be a contributing factor in food induced changes in bioavailability. To identify physicochemical properties of gemfibrozil that may be altered by endogenous and dietary lipids, in vitro studies were conducted in model s...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018967401000
更新日期：1994-12-01 00:00:00
abstract：:The present review discusses drugs and counter ions suitable for ion pair transport (IPT). Ion pairing is shown to effectively increase the lipophilicity and transport rate of polar drugs across lipid membranes. The proposed mechanisms of IPT are discussed in detail. A marked change in drug properties upon ion pair fo...
journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1023/a:1015963128124
更新日期：1989-09-01 00:00:00
abstract：PURPOSE:Since the molecular mechanism of the cell cycle was established, various theoretical models of this process have been developed. A recent study revealed significant variability in cell cycle duration between mother and daughter cells, but this observation has not been incorporated into the theoretical models. ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-019-2570-2
更新日期：2019-02-22 00:00:00
abstract：PURPOSE:This study was aimed at developing a new active loading method to stably encapsulate staurosporine (STS), a water insoluble drug, into lipid-based nanoparticles (LNPs) for drug targeting to tumors. METHODS:A limited amount of DMSO was included during the active loading process to prevent precipitation and faci...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-015-1854-4
更新日期：2016-05-01 00:00:00
abstract：PURPOSE:E-selectin is a cell adhesion molecule that is specifically expressed in the inflammatory vascular endothelium in response to cytokines such as IL-1 beta and TNF-alpha, and interacts with specific ligands containing sialyl Lewis X (Neu5Ac alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc-, SLex). In order to investiga...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018849029727
更新日期：1999-02-01 00:00:00
