A5031417540- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Drug-Induced Hepatotoxicity and Protection
- Aldose Reductase and Taurine
- Influenza Virus Research Studies
- Alcohol Consumption and Health Effects
- Respiratory viral infections research
- Cannabis and Cannabinoid Research
- Neuroscience and Neuropharmacology Research
- Computational Drug Discovery Methods
- Metabolomics and Mass Spectrometry Studies
- Pharmaceutical studies and practices
- Biochemical effects in animals
- Metabolism and Genetic Disorders
- Diet and metabolism studies
- Nuclear Physics and Applications
- Chemical Reactions and Isotopes
- Viral Infections and Immunology Research
- Eicosanoids and Hypertension Pharmacology
- Boron Compounds in Chemistry
- Antiplatelet Therapy and Cardiovascular Diseases
- Epilepsy research and treatment
- Alzheimer's disease research and treatments
- Biochemical and Molecular Research
- Bioinformatics and Genomic Networks
Shionogi (Japan)
2014-2023
Futaba (Japan)
2013-2023
Gifu Pharmaceutical University
1990-1991
Accumulation of amyloid β peptides (Aβ) is thought to be one the causal factors Alzheimer’s disease (AD). The aspartyl protease β-site precursor protein cleaving enzyme 1 (BACE1) rate-limiting for Aβ production, and therefore, BACE1 inhibition a promising therapeutic approach treatment AD. Starting with dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat (JNJ-54861911) as centrally efficacious inhibitor that was advanced into EARLY Phase 2b/3 clinical trial preclinical AD...
3-Deoxyglucosone reductase activity in the extracts of rat, pig and human livers was potently inhibited by aldehyde inhibitors. The major species 3-deoxyglucosone purified from were biochemically immunochemically identical with reductase. two enzymes rat liver exhibited higher catalytic efficiency for than D-glucuronate, a representative substrate
Cell models to investigate intestinal absorption functions, such as those of transporters and metabolic enzymes, are essential for oral drug discovery development. The purpose this study was generate epithelial cells from human induced pluripotent stem (hiPSC-IECs) then clarify whether the functions hydrolase in them reflect small intestine. hiPSC-IECs showed transport activities P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), peptide transporter 1 (PEPT1), revealed by using...
ABSTRACT We evaluated the efficacy of a single intravenous dose peramivir for treatment influenza B virus infection in ferrets and cynomolgus macaques present study. A (60 mg/kg body weight) given to on 1 day postinfection with significantly reduced median area under curve (AUC) titers (peramivir, 8.3 log 10 50% tissue culture infective doses [TCID 50 s]·day/ml; control, 10.7 TCID s·day/ml; P < 0.0001). Furthermore, nasal 2 receiving injection (30 mg/kg) AUCs temperature increase 60 were...
AbstractIn the current study, to understand characteristics of dexamethasone (DEX)-treated female rats as an animal model for drug–drug interactions, a double-cannulation method was applied and separately assessed intestinal hepatic first-pass metabolism midazolam. Midazolam administered intravenously or orally animals, midazolam concentrations in portal systemic plasma were simultaneously determined. Next, rates elimination from intestine liver estimated using AUC values. After oral...
Abstract1. Anti-human cytochrome P450 (CYP) 3A4 antiserum completely inhibited midazolam metabolism in monkey liver microsomes, suggesting that was mainly metabolized by CYP3A enzyme(s) microsomes.2. Midazolam also vitro typical chemical inhibitors of CYP3A, such as ketoconazole, erythromycin and diltiazem, the apparent Ki values for diltiazem were 0.127, 94.2 29.6 μM, respectively.3. increased plasma concentrations when co-administered orally. However, pharmacokinetic parameters not changed...
1. Cytochrome P450 (CYP) 3A catalysis of testosterone 6β-hydroxylation in female rat liver microsomes was significantly induced, then reached a plateau level after pretreatment with 80 mg kg−1 day−1 dexamethasone (DEX) for 3 days.2. Midazolam mainly metabolized by CYP3A DEX-treated from an immuno-inhibition study, and the apparent Km 1.8 μM, similar to that human microsomes.3. Ketoconazole erythromycin, typical inhibitors, demonstrated extensive inhibition midazolam metabolism microsomes, Ki...
Methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) is a novel inhibitor of the ileal apical sodium-dependent bile acid transporter (ASBT/<i>SLC10A2</i>) developed for treatment hypercholesterolemia. The present study investigated hypocholesterolemic action S-8921 glucuronide (S-8921G) in rats. plasma concentration S-8921G was higher than that after single oral administration normal rats, and excreted into (13% dose). Oral either or reduced...
The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice which the immune system suppressed by cyclophosphamide (CP) treatment. mortality rate vehicle control group 100%, and lost 20% their body weight on average day 13 postinfection (p.i.). Repeated administration (40 mg/kg once a day, given intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, loss, viral titers, cytokine production infected compared with...
The immunological relationship of two forms dihydrodiol dehydrogenase (DD) in pig lens to muscle aldose reductase and kidney aldehyde has been studied. Although the minor enzyme form, a monomer Mr 35,000, was identical with reductase, major dimer 65,000, distinct from reductases. species, although their amounts were low, distributed cornea, iris-ciliary body, retina choroid eye. In other mammals, rabbit exhibited much higher DD activity than did mice, rats, cats, hamsters, guinea pigs...
1. The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration [14C]-S-777469 to healthy human subjects.2. Total radioactivity was rapidly well absorbed in humans, with Cmax 11 308 ng eq. S-777469/ml at 4.0 h. AUCinf ratio unchanged total approximately 30%, indicating that extensively metabolized humans.3. metabolite profiling plasma showed 5-carboxymethyl (5-CA) 5-hydroxymethyl (5-HM) the main circulating metabolites, 5-CA 5-HM 24 9.1%, respectively....
1. The drug metabolism and pharmacokinetics of S-777469 were investigated in vitro (rat, dog human) vivo (rats dogs). 2. was rapidly well absorbed, with bioavailability values ranging from 50 to 70% rats dogs, almost all radioactivity excreted into the feces via bile within 48 h. Thus, good (e.g. systemic exposure excretion rate) would be anticipated humans. 3. In qualitatively similar rat, human hepatocytes. acyl glucuronide, 5-hydroxymethyl 4-hydroxycyclohexane main metabolites rats, dogs...
The in vitro and vivo inhibition of cytochrome P450 (CYP) 3A with mechanism-based (MBI) by macrolides was investigated using dexamethasone-treated female rats (DEX-female rats). In the CYP studies erythromycin (ERM) clarithromycin (CAM), similar responses were observed between human DEX-female rat liver microsomes, however, there fewer effects intact male rats. ex study showed that midazolam (MDZ) metabolism microsomes reduced ERM administration inhibitory effect increased increasing doses,...
1. It was previously demonstrated that 10% of S-777469, a cannabinoid receptor 2 selective agonist, is metabolized to its carboxylic acid metabolite (S-777469 5-carboxylic acid, 5-CA) in humans vivo, while the formation 5-CA extremely low human cryopreserved hepatocytes and liver microsomes (HLMs). In this study, factors causing different rates S-777469 vitro vivo were investigated.2. Formation 5-hydroxymethyl (5-HM), precursor 5-CA, catalyzed by CYP2C9. Arachidonic α-linolenic oleic...
Guanfacine is used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), metabolite profiling guanfacine was performed in plasma and urine collected from healthy Japanese adults following repeated oral administration extended-release formulation. Unchanged most abundant component both (from MS signal intensity). In plasma, M3 (a sulfate hydroxy-guanfacine) prominent metabolite; M2 glucuronide a formed by...
The human mass balance of lusutrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, was characterised in seven healthy male subjects after a single oral dose [14C]-lusutrombopag (2 mg, 100 μCi) solution.Lusutrombopag the main component plasma, accounting for 56% plasma radioactivity AUC0-∞. In half-life (70.7 h) longer than that lusutrombopag (25.7 h), suggesting presence long circulating metabolites. excretion pathway lusutorombopag feces, with recovery approximately 83%...
Substrate specificities for the carnitine and glycine conjugates of branched side-chain cyclic carboxylic acids were examined using dog, rabbit, cynomolgus monkey, squirrel monkey hepatocytes kidney slices.For all tested samples, substrate specificity or conjugation showed a similar tendency to those rat experiments reported previously, that is, best conjugate was cyclopropanecarboxylic acid (CPCA), while benzoic (BA), followed by cyclohexanecarboxylic (CHCA).With respect CPCA, highest...
The dehydrogenase activity of dimeric dihydrodiol dehydrogenases (DD) purified from pig and rabbit lenses was inhibited by either L-ascorbic acid or its epimer, isoascorbic acid, at pH 7.5. Isoascorbate [IC50 (concn. giving 50% inhibition) = 0.043 mM for the enzyme; IC50 0.13 enzyme] a more potent inhibitor than ascorbate (IC50 values 0.45 0.90 respectively), but 1 mM-dehydroascorbate gave less 30% inhibition. Glucose, glucuronate, gulono-gamma-lactone, glutathione dithiothreitol did not...