Abstract：
PURPOSE:To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug-drug interaction (DDI) risk using static mechanistic models. METHODS:Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of K(I) and k(inact). Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI. RESULTS:Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The k(inact)/K(I) ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent-drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected. CONCLUSIONS:13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Kenny JR,Mukadam S,Zhang C,Tay S,Collins C,Galetin A,Khojasteh SCdoi
10.1007/s11095-012-0724-6subject
Has Abstractpub_date
2012-07-01 00:00:00pages
1960-76issue
7eissn
0724-8741issn
1573-904Xjournal_volume
29pub_type
杂志文章abstract：:Human serum albumin (HSA) was encapsulated in a 50:50 copolymer of DL-lactide/glycolide in the form of microspheres. These microspheres were used as a model formulation to study the feasibility of controlling the release of large proteins over a 20- to 30-day period. We show that HSA can be successfully incorporated i...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015948829632
更新日期：1990-11-01 00:00:00
abstract：:Microbial metabolism studies of the antimalarial drug arteether (1) have shown that arteether is metabolized by a number of microorganisms. Large-scale fermentation with Aspergillus niger (ATCC 10549) and Nocardia corallina (ATCC 19070) have resulted in the isolation of four microbial metabolites which have been chara...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015845306124
更新日期：1990-02-01 00:00:00
abstract：PURPOSE:The encapsulation of pancreatic β-cells in biocompatible matrix has generated great interest in diabetes treatment. Our work has shown improved microcapsules when incorporating the bile acid ursodeoxycholic acid (UDCA), in terms of morphology and cell viability although cell survival remained low. Thus, the stu...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-016-1863-y
更新日期：2016-05-01 00:00:00
abstract：:The crystal growth kinetics of theophylline monohydrate from aqueous buffered supersaturated solutions were investigated at 10, 20, 30, and 40 degrees C. Crystallization experiments were carried out isothermally at pH 6. During growth the crystal count and size distributions were monitored in situ. The growth rate was...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015817109932
更新日期：1991-05-01 00:00:00
abstract：PURPOSE:N-terminal site-specific mono-PEGylation of recombinant human epidermal growth factor (EGF) was accomplished using polyethyleneglycol (PEG) derivatives (Mw = 2000 and 5000) through a reactive terminal aldehyde group. METHODS:The site-specific PEG conjugation was conducted ata slightly acidic pH condition (pH 5...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1023402123119
更新日期：2003-05-01 00:00:00
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：:A method to provide near-constant sustained release of high molecular weight, water-soluble proteins from polyanhydride microspheres is described. The polyanhydrides used were poly(fatty acid dimer) (PFAD), poly(sebacic acid) (PSA), and their copolymers [P(FAD-SA)]. P(FAD-SA) microspheres containing proteins of differ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018929531410
更新日期：1993-04-01 00:00:00
abstract：PURPOSE:To investigate influence of ion induced mesophasic transformation on pharmaceutical performance of in situ gelling system consisting of glyceryl monooleate. METHODS:The prepared system showed mesophasic transformation during its conversion from sol to gel upon controlled hydration. The process of mesophasic tr...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-013-1033-4
更新日期：2013-07-01 00:00:00
abstract：PURPOSE:The aim of this study was to investigate the effect of hepatic or renal insufficiency on the pharmacokinetics of paclitaxel in rats. METHODS:Rats were treated with carbon tetrachloride (CCl4; 0.5 ml/kg) to induce hepatic failure or were subjected to 5/6 nephrectomy (5/6 Nx) to induce renal failure. Paclitaxel ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-004-1190-6
更新日期：2005-02-01 00:00:00
abstract：:Human monocytes/macrophages (MO/MAC) were isolated from peripheral blood and cultivated on hydrophobic Teflon membranes. This culture system is suitable for HIV infection of MO/MAC in vitro. After transfer into 24-well plates the mature macrophages (infected or uninfected) were used for measurements of phagocytosis. T...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015852732512
更新日期：1992-04-01 00:00:00
abstract：PURPOSE:The lack of an in vivo diagnostic test for AD has prompted the targeting of amyloid plaques with diagnostic imaging probes. We describe the development of a contrast agent (CA) for magnetic resonance microimaging that utilizes the F(ab')2 fragment of a monoclonal antibody raised against fibrillar human Abeta42 ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-008-9600-9
更新日期：2008-08-01 00:00:00
abstract：:Porcine pancreatic elastase, a well-characterized serine protease, has been used as a model to assess the effects of excessive humidity on solid-state stability of the lyophilized protein. Elastase lyophilized without excipients retained full activity immediately after freeze-drying but became denatured upon continued...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018979410338
更新日期：1993-10-01 00:00:00
abstract：PURPOSE:An in vitro dynamic pharmacokinetic (PK) cell culture system was developed to more precisely simulate physiologic nanoparticle/drug exposure. METHODS:A dynamic PK cell culture system was developed to more closely reflect physiologic nanoparticle/drug concentrations that are changing with time. Macrophages were...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-019-2576-9
更新日期：2019-02-01 00:00:00
abstract：PURPOSE:The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetramethylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. METHODS:The study was carried out by investigati...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016055517724
更新日期：1996-02-01 00:00:00
abstract：:Since many chiral pharmaceutical excipients, such as cellulose polymers and cyclodextrins, are used as stationary phases for the separation of enantiomers by high performance liquid chromatography (HPLC), it is hypothesized that one enantiomer of a chiral drug will be released faster than the other from a pharmaceutic...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018937123058
更新日期：1993-11-01 00:00:00
abstract：PURPOSE:To investigate the destruction of clinically-relevant bacteria within biofilms via the sustained release of the antibiotic tetracycline from zein-based electrospun polymeric fibrous matrices and to demonstrate the compatibility of such wound dressing matrices with human skin cells. METHODS:Zein/PCL triple laye...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-015-1782-3
更新日期：2016-01-01 00:00:00
abstract：:The simultaneous diffusion and metabolism of the D- and L-isomers of the aminopeptidase substrate, leucine-p-nitroanilide (LPNA), were examined in vitro in the hamster cheek pouch. L-LPNA was completely hydrolyzed during diffusion across the cheek pouch, whereas D-LPNA crossed the cheek pouch intact. The metabolic bar...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015949614437
更新日期：1989-11-01 00:00:00
abstract：PURPOSE:Interleukin-10 (IL-10) is an anti-inflammatory molecule that has achieved interest as a therapeutic for neuropathic pain. In this work, the potential of plasmid DNA-encoding IL-10 (pDNA-IL-10) slowly released from biodegradable microparticles to provide long-term pain relief in an animal model of neuropathic pa...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-010-0077-y
更新日期：2010-05-01 00:00:00
abstract：PURPOSE:The low aqueous solubility of many drugs impedes detailed investigation as the detection limit of standard testing routines is limited. This is further complicated within application relevant thin films typical used in patches or stripes for buccal or topical routes. METHODS:In this work a model system is deve...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-014-1368-5
更新日期：2014-10-01 00:00:00
abstract：PURPOSE:The aim of this study was to identify the dominant factors affecting the stability of nanoemulsions, using artificial neural networks (ANNs). METHODS:A nanoemulsion preparation of budesonide containing polysorbate 80, ethanol, medium chain triglycerides and saline solution was designed, and the particle size o...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-009-0004-2
更新日期：2010-01-01 00:00:00
abstract：PURPOSE:To investigate plasmid DNA interactions with liposomes prepared from dimyristoylglyceroethylphosphocholine (EDMPC) and DOPE using high sensitivity differential scanning calorimetry (HSDSC). MATERIALS AND METHODS:Large unilamellar liposomes of EDMPC with DOPE (mol ratio 0-50%) were prepared. Plasmid DNA was add...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-007-9325-1
更新日期：2007-10-01 00:00:00
abstract：PURPOSE:To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with 177Lu (trastuzumab-AuNP-177Lu) targeted to HER2 with non-targeted AuNP-177Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection. ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-016-2082-2
更新日期：2017-03-01 00:00:00
abstract：:This paper describes an investigation of the use of poly(lactic/glycolic acid) polymers for long-term delivery of high molecular weight, water-soluble proteins. Poly(lactic/glycolic acid) (PLGA) microspheres, containing (fluorescein isothiocyanate)-labeled bovine serum albumin and (fluorescein isothiocyanate)-labeled ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015841715384
更新日期：1991-06-01 00:00:00
abstract：PURPOSE:Preparation of Nanographene oxide (NGO) - Gelatin hybrids for efficient treatment of Neuroblastoma. METHODS:Nanohybrids were prepared via non-covalent interactions. Spectroscopic tools have been used to discriminate the chemical states of NGO prior and after gelatin coating, with UV visible spectroscopy reveal...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-014-1604-z
更新日期：2015-06-01 00:00:00
abstract：PURPOSE:The objective of this study was to evaluate the in vivo consequences of glycyl-glutamate coadministration on gabapentin oral absorption. METHODS:Rats were administered gabapentin (10 mg/kg plus radiotracer) by gastric gavage, in the absence and presence of dipeptides, and by intravenous administration. Serial ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-007-9272-x
更新日期：2007-08-01 00:00:00
abstract：PURPOSE:The possibility of preparing nanoparticles in the supercooled thermotropic liquid crystalline state from cholesterol esters with saturated acyl chains as well as the incorporation of model drugs into the dispersions was investigated using cholesteryl myristate (CM) as a model cholesterol ester. METHODS:Nanopar...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/b:pham.0000045237.46019.6e
更新日期：2004-10-01 00:00:00
abstract：:Silk is a remarkable biopolymer with a long history of medical use. Silk fabrications have a robust track record for load-bearing applications, including surgical threads and meshes, which are clinically approved for use in humans. The progression of top-down and bottom-up engineering approaches using silk as the basi...
journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1007/s11095-018-2534-y
更新日期：2018-11-05 00:00:00
abstract：:The dose dependency of carbamazepine pharmacokinetics was characterized in rats, a common test animal for antiepileptic drug efficacy. With a randomized Latin square schedule, 5, 10, and 20 mg/kg doses of carbamazepine were injected intravenously into six Sprague-Dawley rats followed by the administration of a 5 or 10...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015872901523
更新日期：1990-05-01 00:00:00
abstract：PURPOSE:To demonstrate the applicability of thermally stimulated current (TSC) spectrometry for the detection of low levels of the amorphous phase in crystalline pharmaceutical materials. METHODS:A crystalline drug substance was melt quenched to produce an amorphous material. Blends of the crystalline and amorphous ph...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1011087012826
更新日期：2001-01-01 00:00:00
abstract：PURPOSE:To study epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 (BP) from a range of single solvent vehicles and evaluate solvent effects on permeability parameters. METHODS:The solubility of BP was measured in a number of solvents. Penetration of BP across human epidermi...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1011958006973
更新日期：1998-12-01 00:00:00
