Abstract：
PURPOSE:To assess the blood-brain barrier (BBB) permeability of 12 clinically-used drugs in mdr1a(+/+) and mdr1a(-/-) mice, and investigate the influence of lipophilicity, nonspecific brain tissue binding, and P-gp-mediated efflux on the rate of brain uptake. METHODS:The BBB partition coefficient (PS) was determined using the in situ mouse brain perfusion technique. The net brain uptake for 12 compounds, and the time course of brain uptake for selected compounds ranging in BBB equilibration kinetics from rapidly-equilibrating (e.g., alfentanil, sufentanil) to slowly-equilibrating (fexofenadine), was determined and compared. RESULTS:There was a sigmoidal relationship in mdr1a(-/-) mice between the log-PS and clogD(7.4) in the range of 0-5. The brain uptake clearance was a function of both permeability and blood flow rate. The brain unbound fraction was inversely proportional to lipophilicity. Alfentanil achieved brain equilibrium approximately 4,000-fold faster than fexofenadine, based on the magnitude of PSxfu,brain. CONCLUSIONS:In situ brain perfusion is a useful technique to determine BBB permeability. Lipophilicity, ionization state, molecular weight and polar surface area are all important determinants for brain penetration. The time to blood-to-brain equilibrium varies widely for different compounds, and is determined by a multiplicity of pharmacokinetic factors.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Zhao R,Kalvass JC,Pollack GMdoi
10.1007/s11095-009-9876-4subject
Has Abstractpub_date
2009-07-01 00:00:00pages
1657-64issue
7eissn
0724-8741issn
1573-904Xjournal_volume
26pub_type
杂志文章abstract：PURPOSE:To determine by pharmacokinetic (PK) means the role of erythropoietin-receptor (EPO-R) upregulation in fetuses on the elimination of erythropoietin (EPO). MATERIALS AND METHODS:Six fetal sheep were catheterized at a gestational age of 125-127 days and phlebotomized daily for 6 days. Paired tracer PK studies us...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-007-9295-3
更新日期：2007-09-01 00:00:00
abstract：PURPOSE:The clinical utility of anthracyclines like idarubicin (IDA) is limited by the occurrence of multidrug resistance and cardiotoxicity. Previous studies have demonstrated that the multidrug transporter P-glycoprotein (P-gp) is present in the heart and have suggested that it exerts a protective function. We sought...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1013022212738
更新日期：2001-11-01 00:00:00
abstract：PURPOSE:The objective of this investigation is to develop a rational design of Osteotropic Drug Delivery System (ODDS), which we have proposed as a novel method for drug delivery to the skeleton via bisphosphonic prodrug, based on the relationship between physicochemical and pharmacokinetic properties of bisphosphonate...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1011033326980
更新日期：2001-05-01 00:00:00
abstract：PURPOSE:Simple uncoated compressed tablets with a central hole (donut-shape) are proposed to provide a constant drug release over a long period of time (> 20 hrs). The effect of hole size and drug solubility on the release kinetics is investigated. METHODS:The donut-shaped polyethylene oxide (PEO, Mw = 4 x 10(6)) tabl...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016218716951
更新日期：1995-07-01 00:00:00
abstract：PURPOSE:Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcom...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-016-1921-5
更新日期：2016-08-01 00:00:00
abstract：PURPOSE:To determine the different conformations of the acyloxyalkoxy-linked cyclic prodrug 1 of the model hexapeptide 2 in solution and to investigate the relationship between these solution conformations and the cellular permeability characteristics of this prodrug. METHODS:Two-dimensional Homonuclear Hartmann-Hahn ...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016484522113
更新日期：1996-11-01 00:00:00
abstract：:Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be "bottom up" as o...
journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1007/s11095-016-2089-8
更新日期：2017-03-01 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：:A rapid quantitative, enantioselective HPLC method for the analysis of the four stereoisomers, (+) and (-) erythro and (+) and (-) threo forms, of mefloquine has been developed using a Chiralpak Ad analytical column containing amylose tris-3,5-dimethylphenyl carbonate coated on silica gel and hexane/ethanol/diethylami...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015832912774
更新日期：1992-12-01 00:00:00
abstract：:The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1018984121415
更新日期：1993-03-01 00:00:00
abstract：PURPOSE:Drug particle physical properties are critical for the efficiency of a drug delivered to the lung. The purpose of this study was to produce ultrafine sumatriptan succinate particles for inhalation. METHODS:Sumatriptan succinate particles were produced via reactive precipitation without any surfactants. Several...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-008-9586-3
更新日期：2008-09-01 00:00:00
abstract：PURPOSE:The purpose of this study was to develop a new computational fluid dynamics (CFD)-based model of the complex transport and droplet drying kinetics within a laboratory-scale spray dryer, and relate CFD-predicted drying parameters to powder aerosolization metrics from a reference dry powder inhaler (DPI). METHOD...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-020-02806-y
更新日期：2020-05-21 00:00:00
abstract：:Significant efforts are made to characterize molecular liabilities and degradation of the drug substance (DS) and drug product (DP) during various product life-cycle stages. The in vivo fate of a therapeutic protein is usually only considered in terms of pharmacokinetics (PKs) and pharmacodynamics (PDs). However, the ...
journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1007/s11095-019-2689-1
更新日期：2020-01-03 00:00:00
abstract：PURPOSE:In this study, modulation of the immune response against diphtheria toxoid (DT) by various adjuvants in transcutaneous immunization (TCI) with microneedle array pretreatment was investigated. METHODS:TCI was performed on BALB/c mice with or without microneedle array pretreatment using DT as a model antigen co-...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-009-9874-6
更新日期：2009-07-01 00:00:00
abstract：PURPOSE:Microphysiological systems (MPS), also known as "organs-on-chips" or "tissue chips," leverage recent advances in cell biology, tissue engineering, and microfabrication to create in vitro models of human organs and tissues. These systems offer promising solutions for modeling human physiology and disease in vitr...
journal_title：Pharmaceutical research
pub_type： 杂志文章,评审
doi：10.1007/s11095-019-2742-0
更新日期：2019-12-17 00:00:00
abstract：PURPOSE:To examine the presence of multiplicity for the biliary excretion of xenobiotic conjugates, we studied the disposition of glycyrrhizin (GR), which has glucuronide within its molecular structure and has the ability to inhibit the biliary excretion of liquiritigenin (LG) glucuronides. METHODS:GR was administered...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016033124819
更新日期：1996-12-01 00:00:00
abstract：PURPOSE:To determine whether LHRH-receptor is expressed in Calu-3, a human bronchial epithelial cell line, and to further determine whether this receptor plays a role in the transport of deslorelin, an LHRH agonist. METHODS:Using cultured monolayers of Calu-3 grown at air-interface, the presence and localization of LH...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/b:pham.0000029294.70707.74
更新日期：2004-06-01 00:00:00
abstract：PURPOSE:It was the purpose of this study to develop a new oral drug delivery system for low molecular weight heparin (LMWH) providing an improved bioavailability and a prolonged therapeutic effect. METHODS:The permeation enhancing polycarbophil-cysteine conjugate (PCP-Cys) used in this study displayed 111.4 +/- 6.4 mi...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1023803706746
更新日期：2003-06-01 00:00:00
abstract：:Semitelechelic poly[N-(2-hydroxypropyl)methacrylamide]s (ST-PHPMA) containing one amino end-group and differing in molecular weight were synthesized by radical polymerization in the presence of 2-aminoethanethiol (AET) as chain transfer agent. These polymers were covalently attached via amide bonds to the surface of n...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016247206531
更新日期：1995-05-01 00:00:00
abstract：PURPOSE:The aim of this work is to design new chitosan conjugates able to self-organize in aqueous solution in the form of micrometer-size platelets. When mixed with amphotericin B deoxycholate (AmB-DOC), micro-platelets act as a drug booster allowing further improvement in AmB-DOC anti-Candida albicans activity. METH...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-017-2117-3
更新日期：2017-05-01 00:00:00
abstract：PURPOSE:Under different charging conditions, particles can be either attracted or repulsed by each other, causing powder agglomeration or segregation. Such behavior can be detrimental in many processes aimed at achieving particulate mixture homogeneity. Consequently, the effects of electrostatic charges on mixing kinet...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-006-9934-0
更新日期：2006-05-01 00:00:00
abstract：:Defined size fractions of polyethyleneglycol powder (MW = 10,000) were mixed with defined size fractions of alpha-lactose monohydrate in order to study the effect of compaction as a function of the weight ratios of the two excipients. For a precise control of the compression cycle, tablets were compressed on a Univers...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015864415693
更新日期：1990-02-01 00:00:00
abstract：:Gallopamil is a calcium-channel antagonist with reported activity in experimental animals three to five times higher than that of verapamil. An automated high-performance liquid chromatographic (HPLC) method with fluorescence detection is described for the simultaneous determination of gallopamil and its metabolite no...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016401405119
更新日期：1987-08-01 00:00:00
abstract：:Penetration of various compounds through shed snake skin was measured in vitro to examine the effect of lipophilicity and molecular size of a compound on permeability through this model membrane. The permeabilities were found to be controlled by the lipophilicity and the molecular size of the permeant. The smaller and...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015902308676
更新日期：1990-12-01 00:00:00
abstract：PURPOSE:Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were exam...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-014-1579-9
更新日期：2015-05-01 00:00:00
abstract：PURPOSE:Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. METHODS:Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice....
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1015314314796
更新日期：2002-05-01 00:00:00
abstract：PURPOSE:The objective of the current study was to investigate whether blood-brain barrier (BBB) permeability studies in vitro could be accelerated by running several compounds together in the same experiment. METHODS:To address this question, we compared the transport of six compounds run separately with the results o...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/b:pham.0000026424.78528.11
更新日期：2004-05-01 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 purpose of this study was to investigate the effects of formulation factors including varying wax concentration, drug loading and drug particle size, on drug release characteristics from both pure oil and gel formulations prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glycer...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016209020160
更新日期：1995-06-01 00:00:00
abstract：PURPOSE:To evaluate different dissolution testing methods and subsequently develop a simple to perform but reproducible and discriminating dissolution technique for inhalative powders. METHODS:From a dry powder a fraction of aerosolized particles with an aerodynamic particle size below 5 μm was collected on regenerate...
journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1007/s11095-012-0744-2
更新日期：2012-08-01 00:00:00
