Abstract:
:In liver microsomes, selexipag (NS-304; ACT-293987) mainly undergoes hydrolytic removal of the sulfonamide moiety by carboxylesterase 1 (CES1) to yield the pharmacologically active metabolite MRE-269 (ACT-333679). However, it is not known how much CES in the liver and intestine contributes to the hydrolysis of selexipag or how selexipag is metabolized in the intestine, including by hydrolysis. To obtain a better understanding of selexipag metabolism in humans, we determined the percentage contribution of CES1 and carboxylesterase 2 (CES2) to the hydrolysis of selexipag and 7 of its analogs with different sulfonamide moieties and evaluated its nonhydrolytic metabolism in human liver microsomes and human intestinal microsomes (HIMS). For selexipag, the percentage contributions of CES1 and CES2 in human liver microsomes were 77.0% and 9.99%, respectively, while the percentage contribution of CES2 in HIMS was 100%. In HIMS, the rate of hydrolysis of selexipag was the lowest among the compounds tested, and no difference between the presence and absence of nicotinamide adenine dinucleotide phosphate was noted. We infer from these results that selexipag is likely to be hydrolyzed by CES2 as well as CES1, and only selexipag itself and the MRE-269 produced by hydrolysis in the intestine would be absorbed after oral administration.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Imai S,Ichikawa T,Sugiyama C,Nonaka K,Yamada Tdoi
10.1016/j.xphs.2018.09.022subject
Has Abstractpub_date
2019-02-01 00:00:00pages
1027-1034issue
2eissn
0022-3549issn
1520-6017pii
S0022-3549(18)30550-1journal_volume
108pub_type
杂志文章abstract::This study reports, for the first time, development of tyrosine kinase inhibitor-loaded, thermosensitive liposomes (TKI/TSLs) and their efficacy for treatment of renal cell carcinoma when triggered by focused ultrasound (FUS). Uptake of these nanoparticles into renal cancer cells was visualized with confocal and fluor...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2017.01.027
更新日期:2017-05-01 00:00:00
abstract::Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to i...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2020.12.018
更新日期:2020-12-23 00:00:00
abstract::The present study pursued to profile the intestinal solubility of nine HIV protease inhibitors (PIs) in fasted- and fed-state human intestinal fluids (FaHIF, FeHIF) aspirated from four volunteers. In addition, the ability of fasted- and fed-state simulated intestinal fluids (FaSSIF, FeSSIF) to predict the intestinal s...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23698
更新日期:2013-10-01 00:00:00
abstract::Free radical polymerization converts aqueous solutions of methacrylated inulin into cross-linked hydrogels. The purpose of this work was to study the hydrogel formation and to characterize the fully cured hydrogels. The gelation process of aqueous solutions of methacrylated inulin was monitored as a function of time b...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js9802796
更新日期:1999-02-01 00:00:00
abstract::Dolasetron mesilate (Anzemet) ((2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1 H-indole-3-carboxylate monomethane-sulfonate) is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The ketone moiety of dolasetron is rapidly reduced...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js960041m
更新日期:1996-07-01 00:00:00
abstract::The clearance (Cl) and volume of distribution (V(ss)) of a lipophilic, lymphatically transported drug, halofantrine (Hf) have been evaluated after intravenous delivery to the systemic circulation in ex vivo lymph and plasma, and compared with the data obtained after administration of a lipid-based emulsion and a lipid...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23211
更新日期:2012-09-01 00:00:00
abstract::This work reports the measurement of the partition rate of a model drug, ibuprofen (IBU), from aqueous solutions into octanol in the absence and presence of common pharmaceutical excipients including glucose, lactose, maltoheptaose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetat...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2018.11.026
更新日期:2019-01-01 00:00:00
abstract::Cellulose derivatives are commonly used as gelling agents in topical and ophthalmic drug formulations. During the course of manufacturing, cellulose derivatives are believed to generate free radicals. These free radicals may degrade the gelling agent, leading to lower viscosity. Free radicals also may react with the a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21632
更新日期:2009-07-01 00:00:00
abstract::At low protein concentrations (c2), non-native protein aggregation rates are known to be sensitive to changes in conformational stability and "weak" or "colloidal" protein-protein interactions. Protein-protein interactions are also known to be strong functions of c2. In the present work, protein-protein interactions a...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2016.01.004
更新日期:2016-03-01 00:00:00
abstract::Hydroxypropyl cellulose films were prepared by compression molding of three different lots of hydroxypropyl cellulose powder at 149 degrees C, 188 degrees C, and 232 degrees C. Rectangular pieces were cut from these films and viscosity average molecular weight (Mv), degree of orientation, and rate of dissolution were ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600740509
更新日期:1985-05-01 00:00:00
abstract::Porcine gelatins have been widely used as stabilizers of macromolecular based pharmaceuticals but the mechanism by which they stabilize has not been precisely established. Their variability and immunogenicity, however, make them less than ideal excipients. In this work, we take advantage of the availability of recombi...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.20980
更新日期:2007-12-01 00:00:00
abstract::The stereochemistries of geometric isomers of 4-(2-bromo-1,2-diphenylvinyl)phenol, 4-(2-bromo-1,2-diphenylvinyl)anisole, and 2-[p-(2-bromo-1,2-diphenylvinyl)phenoxy]triethylamine were determined by conversion of the phenolic analog to the ethers and subsequent comparison of physical properties with those of 2-[p-(2-ch...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600651036
更新日期:1976-10-01 00:00:00
abstract::Eleven quinazolinylformamidines and quinazolinediylbisformamidines were synthesized and investigated for antihypertensive activity in spontaneous hypertensive rats. Several compounds showed moderate antihypertensive activity at 100 mg/kg po. The same compounds were not hypotensive in the normotensive dog. ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600671046
更新日期:1978-10-01 00:00:00
abstract::The problem of optimizing ocular bioavailability of topically applied ophthalmic drugs is discussed. A formula for drug concentration in the tear film is derived using well-known pharmacokinetic relationships and a first-order drug decay model for the tear film. The time integral of the tear film concentration is then...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600800113
更新日期:1991-01-01 00:00:00
abstract::Systematic structural modifications were performed on the natural sesquiterpene lactone tenulin to define those groupings essential to, or significant in, its in vivo antitumor activity. Accordingly, the following tenulin analogs were prepared: dihydrotenulin, 2,3-epoxytenulin, isotenulin, dihydroisotenulin, 2,3-epoxy...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600680616
更新日期:1979-06-01 00:00:00
abstract::The central compartment of an n-compartment mammillary model was concatenated with a gradient compartment (i.e., venous sampling compartment) and with a conventional effect compartment to model arterial-venous drug concentration gradients and the arterial drug concentration vs effect relationship, respectively. To mod...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600840320
更新日期:1995-03-01 00:00:00
abstract::Mechanisms of inhibitory action of sodium salicylate on L-glutamine-D-fructose-6-phosphate aminotransferase, prepared from rat gastric mucosa, were studied. Sodium salicylate at lower concentrations (10-20 mM) inhibited reversibly aminotransferase activity by competing with fructose-6-phosphate. At higher concentratio...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600640711
更新日期:1975-07-01 00:00:00
abstract::To determine how structural changes in antibodies are connected with aggregation, the structural areas of an antibody prone to and/or impacted by aggregation must be identified. In this work, the higher-order structure and biophysical properties of two different monoclonal antibody (mAb) monomers were compared with th...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23754
更新日期:2013-12-01 00:00:00
abstract::The kinetics of decomposition of the following conformationally restricted N-chloro-alpha-amino acids were studied: 1-amino-1-cyclopentanecarboxylic acid (2), 1-amino-1-cyclohexanecarboxylic acid (4), 2-amino-2-norbornanecarboxylic acid (6), and 2-amino-2-benzonorbornanecarboxylic acid (8). The first-order rate consta...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600791216
更新日期:1990-12-01 00:00:00
abstract::A theory of charge, fluid-mass, and solute (including macromolecular) transport through porous media is applied to describe transport phenomena across the external layer of mammalian skin. Linear relationships are derived between transport fluxes and applied fields. These relationships introduce six effective transder...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600830925
更新日期:1994-09-01 00:00:00
abstract::The estimates of infinity values obtained using Prony's method are shown to be subject to significant error arising from small errors in the assigned sample times. The error of the estimate may be reduced by increasing the time interval between samples. ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:
更新日期:1980-10-01 00:00:00
abstract::The complete pH-rate profile of the hydrolysis reaction of aspirin, requiring many experiments in the past, was obtained by a single variable-parameter kinetic experiment carried out by varying the hydrogen ion concentration. The experiment was carried out spectrophotometrically, reading automatically absorbance, pH, ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/1520-6017(200103)90:3<270::aid-jps2>3.0.co
更新日期:2001-03-01 00:00:00
abstract::The S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP (6-CARB-6-MP) prodrugs 5-20 were synthesized from the reaction of 6-MP with N-alkyl-N-alkyoxycarbonylaminomethyl chlorides (4) in dimethyl sulfoxide in overall yields of 5-62%, depending on the N-alkyl and the alkoxy groups involved. The derivatives were fully characte...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600790116
更新日期:1990-01-01 00:00:00
abstract::The aim of this study was to utilize high-speed video imaging for understanding the disintegrability of compacts and disintegrant action upon wetting. High-speed video imaging was used to visualize the disintegration of compacts and effect of wetting on free disintegrant particles. Acquired images were processed using...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.23119
更新日期:2012-06-01 00:00:00
abstract::In this study, we explored the bioavailability in dogs and chemical potency of generic ritonavir and lopinavir/ritonavir tablet products manufactured by various pharmaceutical companies. Chemical potency of the products was examined by HPLC quantitation of ritonavir and lopinavir. Using a dog model, we determined poin...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.21712
更新日期:2010-02-01 00:00:00
abstract::The absorption, protein binding, blood-to-plasma ratio, renal excretion, and pharmacokinetics of the dopamine-2 agonists (D2-agonists) 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone (1), N-(2'-hydroxy-5'-[N,N-di-n-propylaminoethylphenyl])methanesulfonamide (2), and 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone (3...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600751002
更新日期:1986-10-01 00:00:00
abstract::To reduce the risk of immunogenicity that may be caused by therapeutic protein products, it is important to properly characterize subvisible particles and to develop strategies to reduce the levels of particles delivered to patients. In the present study, by using state-of-the-art methods to quantify particle levels, ...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2018.08.022
更新日期:2019-01-01 00:00:00
abstract::The estimation of Michaelis-Menten pharmacokinetic parameters in patients with epilepsy receiving phenytoin continues to be a vexing problem. The various approximate methods suggested in the literature have serious shortcomings, primarily due to the role of the error term in the statistical model. In this report we pr...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1002/jps.2600780514
更新日期:1989-05-01 00:00:00
abstract::Acyclovir is an antiviral drug poorly absorbed in the gastrointestinal tract due to its hydrophilicity, with low oral bioavailability (~20%). Although acyclovir is prescribed in the management of herpes simplex encephalitis (HSE), the disease has a poor prognosis, particularly if the treatment is delayed, reaching mor...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章,评审
doi:10.1016/j.xphs.2021.01.003
更新日期:2021-01-13 00:00:00
abstract::Protein immunogenicity is intensively researched by academics, biopharmaceutical companies, and authorities as it can compromise the safety and efficacy of a biopharmaceutical drug. So far, the exact protein aggregate properties inducing immune responses are not known. Possible protein-related factors could be size, c...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1016/j.xphs.2018.07.022
更新日期:2018-11-01 00:00:00