Abstract:
PURPOSE:To characterize the pharmacokinetics of simvastatin (SV) and simvastatin acid (SVA), a lactone-acid pair known to undergo reversible metabolism, and to better understand mechanisms underlying pharmacokinetic interactions observed between SV and gemfibrozil. METHODS:Pharmacokinetic studies were conducted after intravenous administration of SV and SVA to dogs pretreated with a vehicle or gemfibrozil. In vitro metabolism of SVA in dog hepatocytes as well as in vitro hepatic and plasma conversion of SV/SVA were investigated in the absence and presence of gemfibrozil. RESULTS:In control animals, the irreversible elimination clearances of SV (CL10) and SVA (CL20) were 10.5 and 18.6 ml min(-1) kg(-1), respectively. The formation clearance of SVA from SV (CL12 = 4.8 ml min(-1) kg(-1)) was 8-fold greater than that of SV from SVA (CL21 = 0.6 ml min(-1) kg(-1)), and the recycled fraction was relatively minor (0.009). In gemfibrozil-treated animals, CL10 was essentially unchanged, whereas CL12, CL20, CL21, and recycled fraction were significantly decreased to 2.9, 9, 0.14 ml min(-1) kg(-1), and 0.003, respectively. In control dogs, values for real volume of distribution at steady state (Vss,real) of SV (2.3 L kg(-1)) were much larger than the corresponding values of SVA (0.3 L kg(-1)). Gemfibrozil treatment did not affect Vss,real of either SV or SVA. In dog hepatocytes, gemfibrozil modestly affected the formation of CYP3A-mediated oxidative metabolites (IC50 > 200 microM) and beta-oxidative products (IC5) approximately 100 microM), but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of an SVA beta-oxidation product (IC50 = 18 microM). In in vitro dog and human liver S9 and plasma, hydrolysis of SV to SVA was much faster than that of SVA to SV. Gemfibrozil (250 microM) had a minimal inhibitory effect on the hydrolysis of either SV to SVA or SVA to SV in dog and human liver S9, but had a significant ( approximately 60%) inhibitory effect on the SV to SVA hydrolysis in both dog and human plasma. CONCLUSIONS:In dogs, the interconversion process favored the formation of SVA and was less efficient than the irreversible elimination processes of SV and SVA. Treatment with gemfibrozil did not affect the distribution of SV/SVA, but rather affected the elimination of SVA and the SV/SVA interconversion processes. Gemfibrozil decreased CL20 and CL21 likely via its inhibitory effect on the glucuronidation of SVA, and not on the CYP3A-mediated oxidative metabolism of SV or SVA, the beta-oxidation of SVA, nor the SVA to SV hydrolysis. The decrease in CL12 might be due in part to the inhibitory effect of gemfibrozil on SV to SVA hydrolysis in plasma. Similar rationales may also be applicable to studies in humans and/or other statin lactone-acid pairs.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Prueksaritanont T,Qiu Y,Mu L,Michel K,Brunner J,Richards KM,Lin JHdoi
10.1007/s11095-005-6037-2subject
Has Abstractpub_date
2005-07-01 00:00:00pages
1101-9issue
7eissn
0724-8741issn
1573-904Xjournal_volume
22pub_type
杂志文章abstract:PURPOSE:To investigate the potential of chitosan nanoparticles as a system for improving the systemic absorption of insulin following nasal instillation. METHODS:Insulin-loaded chitosan nanoparticles were prepared by ionotropic gelation of chitosan with tripolyphosphate anions. They were characterized for their size a...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018908705446
更新日期:1999-10-01 00:00:00
abstract:PURPOSE:To investigate the potential of a novel lipid carrier, comprising beads of alpha-cyclodextrin and soybean oil, for topical drug delivery. Adapalene was chosen as a model drug to explore the ability of the beads to encapsulate and release a highly lipophilic compound. MATERIALS AND METHODS:Adapalene-loaded bead...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-007-9395-0
更新日期:2008-02-01 00:00:00
abstract::Micelle-associated epoetin is still a possible explanation for the upsurge of pure red blood cell aplasia associated with subcutaneous use of epoetin alpha in patients with chronic renal failure. ...
journal_title:Pharmaceutical research
pub_type: 评论,信件
doi:10.1007/s11095-006-9573-5
更新日期:2006-03-01 00:00:00
abstract::Various diesters of 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) were screened in order to identify a derivative with improved oral absorption. The solubilities and dissolution rates decreased with increasing chain length and branching of the ester group. However, the dipropionate ester showed an anomalously fas...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016462801968
更新日期:1987-04-01 00:00:00
abstract:PURPOSE:Understanding the mechanism of protein-excipient interaction and illuminating the influencing factors on protein stability are key steps in the rational design of protein formulations. The objective of this study was to assess effects of preferential interaction type of excipient and surface aromatic hydrophobi...
journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2017-07-01 00:00:00
abstract:PURPOSE:Many genetic disorders, including chondrodysplasias, and acquired disorders impair growth plate function, resulting in short and sometimes malformed bones. There are multiple endocrine and paracrine factors that promote chondrogenesis at the growth plate, which could potentially be used to treat these disorders...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-015-1636-z
更新日期:2015-07-01 00:00:00
abstract:PURPOSE:Study the radiolysis of solid-state metoclopramide hydrochloride at various absorbed doses. Elucidate the structure of the degradation products to gain information on the radiolysis mechanisms. METHODS:Solid-state metoclopramide samples were irradiated at several doses with gamma rays and high-energy electrons...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-006-0019-x
更新日期:2006-06-01 00:00:00
abstract:PURPOSE:The aim of this work was to develop PEGylated poly(alkylcyanoacrylate) nanoparticles from a novel methoxypolyethyleneglycol cyanoacrylate-co-hexadecyl cyanoacrylate copolymer. METHODS:PEGylated and non-PEGylated nanoparticles were formed by nanoprecipitation or by emulsion/solvent evaporation. Nanoparticles si...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1011973625803
更新日期:1998-04-01 00:00:00
abstract:PURPOSE:We examined the ability of a protein transduction domain (PTD), YARA, to penetrate in the skin and carry a conjugated peptide, P20. The results with YARA were compared to those of a well-known PTD (TAT) and a control, nontransducing peptide (YKAc). The combined action of PTDs and lipid penetration enhancers was...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-005-2591-x
更新日期:2005-05-01 00:00:00
abstract:PURPOSE:Evaluate the ability of (-)-6-aminocarbovir ((-)-6AC) to improve the CNS exposure to (-)-carbovir ((-)-CBV). METHODS:Activation of (-)-6AC in vitro was assessed by incubations of rat brain tissue homogenates. The in vivo brain exposure to (-)-CBV was then examined in rats after iv infusions of either (-)-CBV (...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016229624703
更新日期:1995-06-01 00:00:00
abstract::A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transp...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016212804288
更新日期:1995-03-01 00:00:00
abstract::The application of supercritical fluid (SF) processing in pharmaceutical research is increasing particularly in the field of particle formation for drug delivery systems. The SF processes have benefits over the existing particle formation methods in terms of improved control, flexibility and operational ease. This rev...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
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更新日期:1999-07-01 00:00:00
abstract:PURPOSE:Solid lipid nanoparticles (SLNs) have been proposed as a colloidal carrier system that could enhance the oral bioavailability of curcumin. However, a burst release of the loaded drug, which occurs in acidic environments, has been a main obstacle to the oral delivery of curcumin by using SLNs as a carrier system...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-014-1469-1
更新日期:2015-02-01 00:00:00
abstract:PURPOSE:The prognosis for glioma patients is poor, and development of new treatments is critical. Previously, we engineered polymer-based vaccines that control GM-CSF, CpG-oligonucleotide, and tumor-lysate presentation to regulate immune cell trafficking and activation, which promoted potent immune responses against pe...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-010-0361-x
更新日期:2011-05-01 00:00:00
abstract::During protein lyophilization, it is common practice to complete the freezing step as fast as possible in order to avoid protein denaturation, as well as to obtain a final product of uniform quality. We report a contradictory observation made during lyophilization of recombinant tissue-type plasminogen activator (t-PA...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016270103863
更新日期:1995-01-01 00:00:00
abstract:PURPOSE:The rapid oxidation of rofecoxib under alkaline conditions has been previously reported. The oxidation was reported to involve gamma-lactone ring opening to an alcohol, which further oxidized to a dicarboxyclic acid. The oxidation was suspected to be mediated by peroxy radicals. This work further investigates t...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-005-6947-z
更新日期:2005-10-01 00:00:00
abstract::A method is described for the assay of phenobarbital N-glucosylation using UDP-D-[6-3H]glucose. The radioactive phenobarbital N-glucoside conjugates [(5R)-PBG, (5S)-PBG] formed during the incubations were resolved from each other and from uncharacterized radioactive products by semipreparative HPLC. The product ratio ...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015889707922
更新日期:1992-05-01 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
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1020354809581
更新日期:2002-09-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-012-0854-x
更新日期:2013-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2007-03-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2009-09-01 00:00:00
abstract::The influence of the jejunal bloodflow on the absorption of theophylline was investigated. The bloodflow through a segment under investigation was varied by changing the systemic blood pressure by means of a donor blood infusion into the jugular vein or by an infusion of isoprenaline or levarterenol into a femoral vei...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/A:1016374508542
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:Indocyanine green (ICG), an FDA-approved near infrared (NIR) dye, has potential application as a contrast agent for tumor detection. Because ICG binds strongly to plasma proteins and exhibits aqueous, photo, and thermal instability, its current applications are largely limited to monitoring blood flow. To addre...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-010-0190-y
更新日期:2010-09-01 00:00:00
abstract::The use of microdialysis sampling to study the binding of drugs to plasma proteins was evaluated. Microdialysis sampling is accomplished by placing a short length of dialysis fiber in the sample and perfusing the fiber with a vehicle. Small molecules in the sample, such as drugs, diffuse into the fiber and are transpo...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015955503708
更新日期:1990-10-01 00:00:00
abstract:PURPOSE:The Caco-2 association of lectin-grafted PLGA-nanospheres was investigated compared to plain and BSA-coated spheres. METHODS:Nanospheres made from fluorescent-labeled PLGA were coated with wheat germ agglutinin (WGA) or BSA and incubated with Caco-2 monolayers varying the concentration of nanospheres, the time...
journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/b:pham.0000045247.09724.26
更新日期:2004-10-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016088424993
更新日期:1996-03-01 00:00:00
abstract:PURPOSE:Tumor vascular normalization by antiangiogenic agents may increase tumor perfusion but reestablish vascular barrier properties in CNS tumors. Vascular priming via nanoparticulate carriers represents a mechanistically distinct alternative. This study investigated mechanisms by which sterically-stabilized liposom...
journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2012-12-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1999-06-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1995-07-01 00:00:00