[Verification of Pharmaceutical Education System Reform].

The pharmaceutical education system underwent major changes in 2006 by extending the period of completion to six years. The decision was made by a resolution in the Diet, but a supplementary resolution was submitted at that time. In this paper, we discussed whether on-site pharmaceutical education complies with the accompanying resolution.

Virtual Reality Images of the Home Are Useful for Patients With Hospital-Based Palliative Care: Prospective Observational Study With Analysis by Text Mining.

Background: Malignancy patients who need long-term hospitalization can feel loneliness affecting their quality of life. The global COVID-19 pandemic has caused visiting restrictions that could mean patients who might be missing out on family support and palliative care, therefore, need to adapt and change. We used virtual reality (VR) technology with the aim of reducing feelings of loneliness among these patients.

Methylmercury Decreases AMPA Receptor Subunit GluA2 Levels in Cultured Rat Cortical Neurons.

Methylmercury (MeHg) is a well-known environmental pollutant that has harmful effects on the central nervous systems of humans and animals. The molecular mechanisms of MeHg-induced neurotoxicity at low concentrations are not fully understood. Here, we investigated the effects of low-concentration MeHg on the cell viability, Ca homeostasis, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2 levels, which determine Ca permeability of AMPA receptors, in rat primary cortical neurons.

Xanthine oxidase and aldehyde oxidase contribute to allopurinol metabolism in rats.

Background: Allopurinol is used to treat hyperuricemia and gout. It is metabolized to oxypurinol by xanthine oxidase (XO), and aldehyde oxidase (AO). Allopurinol and oxypurinol are potent XO inhibitors that reduce the plasma uric acid levels.

Improved Predictability of Hepatic Clearance with Optimal pH for Acyl-Glucuronidation in Liver Microsomes.

The purpose of this study was to investigate the optimal pH for acyl-glucuronidation formation with carboxylic acid-containing compounds in human and rat liver microsomes to improve the predictability of their hepatic clearance. The optimal pH for acyl-glucuronidation of all 17 compounds was around pH 6.0 in human and rat liver microsomes.

Assessment of metabolic activation of felbamate in chimeric mice with humanized liver in combination with in vitro metabolic assays.

Felbamate (FBM) is an antiepileptic drug that has minimal toxicity in preclinical toxicological species but has a serious idiosyncratic drug toxicity (IDT) in humans. The formation of reactive metabolites is common among most drugs associated with IDT, and 2-phenylpropenal (2-PP) is believed to be the cause of IDT by FBM. It is important to consider the species difference in susceptibility to IDT between experimental animals and humans.

Involvement of aldehyde oxidase in the metabolism of aromatic and aliphatic aldehyde-odorants in the mouse olfactory epithelium.

Xenobiotic-metabolizing enzymes (XMEs) expressed in the olfactory epithelium (OE) are known to metabolize odorants. Aldehyde oxidase (AOX) recognizes a wide range of substrates among which are substrates with aldehyde groups. Some of these AOX substrates are odorants, such as benzaldehyde and n-octanal.

Amiodarone bioconcentration and suppression of metamorphosis in Xenopus.

Trace concentrations of a number of pharmaceutically active compounds have been detected in the aquatic environment in many countries, where they are thought to have the potential to exert adverse effects on non-target organisms. Amiodarone (AMD) is one such high-risk compound commonly used in general hospitals. AMD is known to alter normal thyroid hormone (TH) function, although little information is available regarding the specific mechanism by which this disruption occurs.

Predictability of human pharmacokinetics of drugs that undergo hepatic organic anion transporting polypeptide (OATP)-mediated transport using single-species allometric scaling in chimeric mice with humanized liver: integration with hepatic drug metabolism.

We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CL), distribution volumes in steady state (Vd) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present study, we examined eight compounds (bosentan, cerivastatin, fluvastatin, pitavastatin, pravastatin, repaglinide, rosuvastatin, valsartan) as typical organic anion transporting polypeptide (OATP) substrates and six compounds metabolized by P450 and non-P450 enzymes to evaluate the predictability of CL, Vd and plasma concentration-time profiles after intravenous administration to chimeric mice. The predicted CL and Vd of drugs that undergo OATP-mediated uptake and P450/non-P450-mediated metabolism reflected the observed data from humans within a threefold error range.

Activation of PXR, CAR and PPARα by pyrethroid pesticides and the effect of metabolism by rat liver microsomes.

In this study, we used reporter gene assays in COS-1 cells to examine the activation of rat pregnane X receptor (PXR), rat constitutive androstane receptor (CAR) and rat peroxisome-proliferator activated receptor (PPAR)α by pyrethroid pesticides, and to understand the effects of metabolic modification on their activities. All eight pyrethroids tested in this study showed rat PXR agonistic activity; deltamethrin was the most potent, followed by permethrin and cypermethrin. However, when the pyrethroids were incubated with rat liver microsomes, their rat PXR activities were decreased to various extents.

Comparative study of the effect of 17 parabens on PXR-, CAR- and PPARα-mediated transcriptional activation.

Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity.

Changes in Bile Acid Concentrations after Administration of Ketoconazole or Rifampicin to Chimeric Mice with Humanized Liver.

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis.

Coordinated cytochrome P450 expression in mouse liver and intestine under different dietary conditions during liver regeneration after partial hepatectomy.

Liver resection is performed to remove tumors in patients with liver cancer, but the procedure's suitability depends on the regenerative ability of the liver. It is important to consider the effects of exogenous factors, such as diets, on liver regeneration for the recovery of function. The evaluation of drug metabolism during liver regeneration is also necessary because liver dysfunction is generally observed after the operation.

Utility of Chimeric Mice with Humanized Liver for Predicting Human Pharmacokinetics in Drug Discovery: Comparison with in Vitro-in Vivo Extrapolation and Allometric Scaling.

Predicting human pharmacokinetics (PK) such as clearance (CL) and volume of distribution (Vd) is a critical component of drug discovery. These predictions are mainly performed by in vitro-in vivo extrapolation (IVIVE) using human biological samples, such as hepatic microsomes and hepatocytes. However, some issues with this process have arisen, such as inconsistencies between in vitro and in vivo findings; the integration of predicted CYP, non-CYP and transporter-mediated human PK; and the difficulty of evaluating very metabolically stable compounds.

Inhibition of cytochrome P450 3A protein degradation and subsequent increase in enzymatic activity through p38 MAPK activation by acetaminophen and salicylate derivatives.

Cytochrome P450 (CYP) 3A4 plays an important role in drug metabolism. Although transcriptional regulation of CYP3A expression by chemicals has been comprehensively studied, its post-translational regulation is not fully understood. We previously reported that acetaminophen (APAP) caused accumulation of functional CYP3A protein via inhibition of CYP3A protein degradation through reduction of glycoprotein 78 (gp78), an E3 ligase of the ubiquitin proteasome system.

[Contribution of chimeric mice with a humanized liver to the evaluation of pharmacology, toxicity, and pharmacokinetics in drug discovery and development].

To develop new drugs with high efficacy and safety, it is important to predict the pharmacological, toxicological, and pharmacokinetic profiles of drug candidates in humans. Chimeric mice with a humanized liver are mice in which human hepatocytes have been transplanted, such that mouse liver cells are replaced with human hepatocytes; these mice have been used as prediction models. Studies performed thus far indicate that chimeric mice with a humanized liver can be used for the prediction of human-specific metabolite formation and plasma concentration-time curves for several drugs.

Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions.

As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O-benzylguanine as substrates.

Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures.

Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells.

Tributyltin induces epigenetic changes and decreases the expression of nuclear respiratory factor-1.

Tributyltin (TBT), a common organotin environmental pollutant, has been widely used as a component of marine antifouling paints. We previously reported that exposure to TBT inhibits the expression and DNA binding of nuclear respiratory factor-1 (NRF-1) and causes neurotoxicity. In the present study, we focused on the epigenetic effects of TBT and investigated whether TBT decreases NRF-1 expression via epigenetic modifications in SH-SY5Y human neuroblastoma cells.

Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals.

Developmental changes in drug-metabolizing enzyme expression during metamorphosis of Xenopus tropicalis.

A large number of chemicals are routinely detected in aquatic environments, and these chemicals may adversely affect aquatic organisms. Accurate risk assessment requires understanding drug-metabolizing systems in aquatic organisms because metabolism of these chemicals is a critical determinant of chemical bioaccumulation and related toxicity. In this study, we evaluated mRNA expression levels of nuclear receptors and drug-metabolizing enzymes as well as cytochrome P450 (CYP) activities in pro-metamorphic tadpoles, froglets, and adult frogs to determine how drug-metabolizing systems are altered at different life stages.

Assessment of amiodarone-induced phospholipidosis in chimeric mice with a humanized liver.

It is important to consider susceptibility to drug-induced toxicity between animals and humans. Chimeric mice with a humanized liver are expected to predict hepatotoxicity in humans. Drug-induced phospholipidosis (DIPL), in which phospholipids accumulate, is a known entity.

Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition.

Tributyltin (TBT), which has been widely used as an antifouling agent in paints, is a common environmental pollutant. Although the toxicity of high-dose TBT has been extensively reported, the effects of low concentrations of TBT are relatively less well studied. We have previously reported that low-concentration TBT decreases α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptor subunit 2 () expression in cortical neurons and enhances neuronal vulnerability to glutamate.

Purification of monoclonal antibodies entirely in flow-through mode.

A depth filter is widely used in biopharmaceutical manufacturing process. In this study, we found that buffer exchange to reduce conductivity dramatically improved the removal of impurities in depth filtration. The host cell protein clearance was comparable to that of protein A affinity chromatography, which is generally used as a first capture step in monoclonal antibody purification.

Carbofuran causes neuronal vulnerability to glutamate by decreasing GluA2 protein levels in rat primary cortical neurons.

Glutamate receptor 2 (GluA2/GluR2) is one of the four subunits of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR); an increase in GluA2-lacking AMPARs contributes to neuronal vulnerability to excitotoxicity because of the receptor's high Ca permeability. Carbofuran is a carbamate pesticide used in agricultural areas to increase crop productivity. Due to its broad-spectrum action, carbofuran has also been used as an insecticide, nematicide, and acaricide.