Abstract:
:The antiviral drug tenofovir (TFV) is orally administered as the fumarate salt of its disoproxil prodrug (TFV disoproxil fumarate (TDF)). TFV is a dianion at physiological pH and, as a result, has poor lipid membrane permeability. Administration of the lipophilic and cell-permeable prodrug, TFV disoproxil, enhances the oral absorption of TFV. In order to determine whether oral administration of TDF also increases distribution to sites of viral infection, the plasma and circulating lymphoid cell pharmacokinetics of TFV and its phosphorylated metabolites were assessed following a single oral TDF or subcutaneous TFV administration at doses yielding equivalent plasma exposures to TFV in macaques. Despite TFV disoproxil's lack of plasma stability and undetectable levels in the first plasma samples taken, oral administration of TDF resulted in 7.9-fold higher peripheral blood mononuclear cell exposures to the active metabolite, TFV-diphosphate. The apparent plasma terminal half-life (t(1/2)) of TFV was also longer following oral TDF relative to subcutaneous TFV administration (median t(1/2) of 15.3 and 3.9 h, respectively), suggesting broader distribution to cells and tissues outside of the central plasma compartment. In conclusion, the disoproxil pro-moiety enhances not only the oral absorption of TFV but also tissue and lymphoid cell loading. These results illustrate that administration of even a fleeting prodrug can increase target tissue loading and give valuable insight for future prodrug development.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Durand-Gasselin L,Van Rompay KK,Vela JE,Henne IN,Lee WA,Rhodes GR,Ray ASdoi
10.1021/mp900036ssubject
Has Abstractpub_date
2009-07-01 00:00:00pages
1145-51issue
4eissn
1543-8384issn
1543-8392journal_volume
6pub_type
杂志文章abstract::Powder adhesion or sticking onto punches is one of the outstanding issues in pharmaceutical tablet manufacturing. We show in this work that, at comparable particle sizes, the acesulfame potassium exhibited pronouncedly reduced propensity to punch sticking than acesulfame. Detailed analyses revealed strong correlation ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00247
更新日期:2019-06-03 00:00:00
abstract::Porous silicon microparticles presenting pathogen-associated molecular patterns mimic pathogens, enhancing internalization of the microparticles and activation of antigen presenting dendritic cells. We demonstrate abundant uptake of microparticles bound by the TLR-4 ligands LPS and MPL by murine bone marrow-derived de...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3001292
更新日期:2012-07-02 00:00:00
abstract::Despite significant potential of oligonucleotides (ONs) for therapeutic and diagnostic applications, rapid and widespread intracellular delivery of ONs in cells situated in tissues such as skin, head and neck cavity, and eye has not been achieved. This study was aimed at evaluating the synergistic combination of micro...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300717f
更新日期:2013-08-05 00:00:00
abstract::The current regimen of factor IX (FIX) injection is of an episodic format, which leads to limited efficacy. A sustained release dosage form is beneficial in terms of reducing the injection frequency and improving the therapeutic effectiveness. The aim of this study was to formulate a new microsphere form of a FIX-cont...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200133s
更新日期:2011-10-03 00:00:00
abstract::Novel multivalent copper(II)-conjugated phosphorus dendrimers and their corresponding mononuclear copper(II) complexes were synthesized, characterized, and screened for antiproliferative activity against human cancer cell lines. Selected copper ligands were grafted on the surface of phosphorus dendrimers of generation...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp4000184
更新日期:2013-04-01 00:00:00
abstract::Dissolution is a crucial process for the oral delivery of drug products. Before being absorbed through epithelial cell membranes to reach the systemic circulation, drugs must first dissolve in the human gastrointestinal (GI) tract. In vivo and in vitro dissolutions are complex because of their dependency upon the drug...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00614
更新日期:2020-10-05 00:00:00
abstract::The potential use of poly(dimethylsiloxane) (PDMS) as an in vitro biomimetic analogue of the passive drug absorption process in the human gastrointestinal tract (GI) is assessed. PDMS is biomimetic because of similarities in small molecule transport, such as mechanism, ionization selectivity, lipophilicity. Nine molec...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00798
更新日期:2017-12-04 00:00:00
abstract::Modifying nanoparticles with targeting peptides which can specifically bind to intestinal epithelium was recently suggested as a strategy to further enhance their ability for the oral delivery of macromolecular drugs. However, few studies were focused on comprehensive understanding of the uptake and transport processe...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400685v
更新日期:2014-05-05 00:00:00
abstract::We evaluated the chemical and enzymatic stabilities of prodrugs containing methoxy, ethoxy and propylene glycol linkers in order to find a suitable linker for prodrugs of carboxylic acids with amino acids. l-Valine and l-phenylalanine prodrugs of model compounds (benzoic acid and phenyl acetic acid) containing methoxy...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900084v
更新日期:2009-09-01 00:00:00
abstract::Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles have a proven capacity for drug solubilization and have entered phase III clinical trials as a substitute for Cremophor EL in the delivery of paclitaxel in cancer therapy. PEG-b-PLA is less toxic than Cremophor EL, enabling a doubling of paclitaxel...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp2000549
更新日期:2011-08-01 00:00:00
abstract::Cold crystallization of amorphous pharmaceuticals is an important aspect in the search to stabilize amorphous or glassy compounds used as amorphous pharmaceutical ingredients (APIs). In the present work, we report results for the isothermal crystallization of the compound GDC-0276 based on differential scanning calori...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00776
更新日期:2021-01-04 00:00:00
abstract::Improving the therapeutic index of anticancer agents is an enormous challenge. Targeting decreases the side effects of the therapeutic agents by delivering the drugs to the intended destination. Nanocarriers containing the nuclear localizing peptide sequences (NLS) translocate to the cell nuclei. However, the nuclear ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00014
更新日期:2017-06-05 00:00:00
abstract::In humans, C-X-C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4-CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation fo...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00069
更新日期:2019-05-06 00:00:00
abstract::Although nitric oxide (NO) is a bactericidal component of the macrophage's innate response to intracellular infections such as tuberculosis (TB), prolonged inhalation of NO gas has little benefit in chemotherapy of TB. The impact of controlled release of NO through intracellular delivery of NO donors to macrophages in...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300269g
更新日期:2012-11-05 00:00:00
abstract::The present work reports a thorough conformational analysis of iodinated contrast media: iomeprol, iopamidol (the world's most utilized contrast agent), and iopromide. Its main aim is the understanding of the complex structural features of these atropisomeric molecules, characterized by the presence of many conformers...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp5007486
更新日期:2015-06-01 00:00:00
abstract::Therapeutic monoclonal antibodies are currently delivered mainly via the intravenous route, since large volumes are often required to deliver a therapeutic dose. Administration via the subcutaneous route would have several therapeutic advantages; the absorption mechanisms for antibodies dosed subcutaneously are poorly...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400464s
更新日期:2014-02-03 00:00:00
abstract::Iron oxide nanoparticles have great potential as diagnostic and therapeutic agents in cancer and other diseases; however, biological aggregation severely limits their function in vivo. Aggregates can cause poor biodistribution, reduced heating capability, and can confound their visualization and quantification by magn...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00866
更新日期:2016-07-05 00:00:00
abstract::The systemic pharmacokinetics and pharmacodynamics of small molecules are determined by subcellular transport phenomena. Although approaches used to study the subcellular distribution of small molecules have gradually evolved over the past several decades, experimental analysis and prediction of cellular pharmacokinet...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp200092v
更新日期:2011-10-03 00:00:00
abstract::Whether luteolin inhibits HBV replication has not been validated and the underlying mechanism of which has never been elucidated. In this study, we show that luteolin reduces HBV DNA replication in HepG2.2.15 cells. Luteolin effectively inhibited the expression of hepatocyte nuclear factor 4α (HNF4α) and its binding t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00789
更新日期:2016-02-01 00:00:00
abstract::Targeted therapies are emerging as a preferred strategy for treatment of cancer and other diseases. To evaluate the effect of high affinity receptors on the rate and extent of tumor penetration of receptor-targeted drugs, we have characterized the kinetics of folate-rhodamine uptake by folate receptor (FR)-expressing ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900158d
更新日期:2009-11-01 00:00:00
abstract::Accumulating evidence suggests that EphB4 plays key roles in cancer progression in numerous cancer types. In fact, therapies focusing on EphB4 have become potentially important components of various cancer treatment strategies. However, tumor sensitivity to EphB4 suppression may not be uniform for different cancers. I...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300461b
更新日期:2013-01-07 00:00:00
abstract::Conjugation with a cell penetrating peptide such as Tat presents an effective approach to improve the intracellular accumulation of molecules with low membrane permeability. This strategy, however, leads to a reduced cellular entry of molecules that can cross cell membrane effectively. We report here that covalent lin...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400619v
更新日期:2014-03-03 00:00:00
abstract::Abnormal tumor vessels impede the transport and distribution of chemotherapeutics, resulting in low drug concentration at tumor sites and compromised drug efficacy. Normalizing tumor vessels can modulate tumor vascular permeability, alleviate tumor hypoxia, increase blood perfusion, attenuate interstitial fluid pressu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00475
更新日期:2017-10-02 00:00:00
abstract::This study describes a novel nonlinear variant of the well-known Yalkowsky general solubility equation (GSE). The modified equation can be trained with small molecules, mostly from the Lipinski Rule of 5 (Ro5) chemical space, to predict the intrinsic aqueous solubility, S0, of large molecules (MW > 800 Da) from beyond...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00689
更新日期:2020-10-05 00:00:00
abstract::Myeloid differentiation primary response 88 (MyD88) is an intracellular adaptor protein central to the signaling of multiple receptors involved in inflammation. Since innate immune inflammation promotes autoimmunity, MyD88 is an attractive target in autoimmune disease. We previously developed c(MyD 4-4), a novel cycli...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01180
更新日期:2019-04-01 00:00:00
abstract::Intracellular unbound drug concentrations determine affinity to targets in the cell interior. However, due to difficulties in measuring them, they are often overlooked in pharmacology. Here we present a simple experimental technique for the determination of unbound intracellular drug concentrations in cultured cells t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp4000822
更新日期:2013-06-03 00:00:00
abstract::Peptide nucleic acids have a number of features that make them an ideal platform for the development of in vitro biological probes and tools. Unfortunately, their inability to pass through membranes has limited their in vivo application as diagnostic and therapeutic agents. Herein, we describe the development of catio...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp800199w
更新日期:2009-03-01 00:00:00
abstract::Nanoenabled lipid-based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00097
更新日期:2018-07-02 00:00:00
abstract::PCPP, a well-defined polyphosphazene macromolecule, has been studied as an immunoadjuvant for a soluble form of the postfusion glycoprotein of respiratory syncytial virus (RSV sF), which is an attractive vaccine candidate for inducing RSV-specific immunity in mice and humans. We demonstrate that RSV sF-PCPP formulatio...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00118
更新日期:2017-07-03 00:00:00
abstract::The biodistribution of dendronized iron oxides, NPs10@D1_DOTAGA and melanin-targeting NPs10@D1_ICF_DOTAGA, was studied in vivo using magnetic resonance imaging (MRI) and planar scintigraphy through [177Lu]Lu-radiolabeling. MRI experiments showed high contrast power of both dendronized nanoparticles (DPs) and hepatobil...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00904
更新日期:2018-02-05 00:00:00