RESUMO
Recent developments in research concerning metal-organic frameworks and coordination polymers have provided the successful design of charge-variable molecular frameworks. However, few comprehensive studies exist that investigate the control of charge states in series of molecular frameworks such as these. Herein, we discuss the ionicity diagrams of two series containing electron-donor (D) and -acceptor (A) units: one-dimensional DA chains and two-dimensional D2A layers. The series were obtained by reacting paddlewheel-type diruthenium(II,II) complexes ([Ru2II,II]), which served as D units, with the polycyano-organic acceptors N,N'-dicyanoquinodiimine (DCNQI) and 7,7,8,8-tetracyano-p-quinodimethane (TCNQ), which served as A units. Fifteen novel members of neutral charged DA chains were fabricated in this study to characterize the ionicity diagrams for DA and D2A systems.
RESUMO
A new ionic donor-acceptor (D+ A- ) chain compound, [{Ru2 (2,6-(CF3 )2 PhCO2 )2 (p-PhPhCO2 )2 }DMDCNQI] (1; 2,6-(CF3 )2 PhCO2- =2,6-bis(trifluoromethyl)benzoate; p-PhPhCO2- =4-biphenylcarboxylate; DMDCNQI=2,5-dimethyl-N,N'-dicyanoquinonediimine) was isolated and structurally characterized. It represents the first of this type of ionic chain compounds.
RESUMO
Recently, protein-facilitated uptake has been suggested to be an important factor in the precise prediction of the pharmacokinetic (PK) profiles of drugs. In our previous study, a physiologically-based pharmacokinetic (PBPK) approach considering the mechanism of albumin-mediated hepatic uptake was developed for predicting human PK profiles. It was assumed that drugs affected by albumin-mediated hepatic uptake would bind only to albumin, which means that there would be over-estimation of the contribution of protein-facilitated uptake for a drug that could bind to multiple proteins. In this study, we developed a method that can evaluate the albumin binding fraction in plasma considering the affinity for other proteins. Based on the albumin binding fraction, the contribution of albumin-mediated hepatic uptake was theoretically estimated, and then the human PK profiles were predicted by our proposed PBPK approach incorporating this mechanism. As a result, the predicted human PK profiles agreed well with the observed ones, and the absolute average fold error of PK parameters was almost within a 1.5-fold error on average. These findings show the importance of considering protein-facilitated uptake and also suggest that our proposed PBPK approach can be useful in scientific discussions with regulatory authorities.
Assuntos
Modelos Biológicos , Preparações Farmacêuticas , Albuminas/metabolismo , Transporte Biológico , Humanos , Fígado/metabolismo , Preparações Farmacêuticas/metabolismo , FarmacocinéticaRESUMO
We aimed to establish an in vitro differentiation procedure to generate matured small intestinal cells mimicking human small intestine from human-induced pluripotent stem cells (iPSCs). We previously reported the efficient generation of CDX2-expressing intestinal progenitor cells from embryonic stem cells (ESCs) using 6-bromoindirubin-3'-oxime (BIO) and (3,5-difluorophenylacetyl)-L-alanyl-L-2-phenylglycine tert-butyl ester (DAPT) to treat definitive endodermal cells. Here, we demonstrate the generation of enterocyte-like cells by culturing human iPSC-derived intestinal progenitor cells on a collagen vitrigel membrane (CVM) and treating cells with a simple maturation medium containing BIO, DMSO, dexamethasone, and activated vitamin D3. Functional tests further confirmed that these iPSC-derived enterocyte-like cells exhibit P-gp- and BCRP-mediated efflux and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. We concluded that hiPS cell-derived enterocyte-like cells can be used as a model for the evaluation of drug transport and metabolism studies in the human small intestine.
Assuntos
Técnicas de Cultura de Células/métodos , Enterócitos/citologia , Enterócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Diferenciação Celular , Linhagem Celular , Células Cultivadas , Colágeno/metabolismo , Meios de Cultura , Citocromo P-450 CYP3A/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Adulto JovemRESUMO
Naloxone is a µ-opioid receptor antagonist that has been used to prevent overdose-related respiratory depression and deaths by the illicit use of opioids. Naloxone can also deter the abuse potential of opioids, but little has been reported regarding its antagonistic activity profile against opioid-induced psychological dependence. This study aimed to confirm the antagonistic activity profile of naloxone against several µ-opioid receptor agonists and investigate whether naloxone could affect the psychological dependence induced by widely used µ-opioid receptor agonist, oxycodone. In the Guanosine-5'-o-(3-thio) triphosphate (GTPγS) binding assay, naloxone (30-30,000â¯nM) inhibited the GTPγS binding induced by oxycodone, hydrocodone, morphine, and fentanyl. It elicited parallel rightward shifts in the concentration-response curves, indicating that naloxone possessed a competitive antagonistic activity profile against these µ-opioid receptor agonists. In the conditioned place preference test, oxycodone (0.01-1â¯mg/kg, i.v.) produced dose-dependent increases in place preference. The increased place preference induced by oxycodone (1â¯mg/kg) was significantly attenuated by co-administration of naloxone at a dose of 0.5â¯mg/kg but not 0.01â¯mg/kg. Naloxone (0.5â¯mg/kg, i.v.) also blocked oxycodone (1â¯mg/kg)-induced dopamine release in nucleus accumbens; however, at a lower dose (0.01â¯mg/kg), it did not affect the intrinsic dopamine release by oxycodone. These results indicate that the psychological dependence of oxycodone could be antagonized by naloxone, depending on the dose. This characterization might lead to a better understanding of the competitive antagonistic activity profile of naloxone for µ-opioid receptor in the brain.