Development of a novel gut microphysiological system that facilitates assessment of drug absorption kinetics in gut.

There is an urgent need for novel methods that can accurately predict intestinal absorption of orally administered drugs in humans. This study aimed to evaluate the potential of a novel gut microphysiological system (MPS), gut MPS/Fluid3D-X, to assess the intestinal absorption of drugs in humans. The gut MPS/Fluid3D-X model was constructed using a newly developed flow-controllable and dimethylpolysiloxane-free MPS device (Fluid3D-X).

Effect of Rifampicin on the Plasma Concentrations of Bile Acid-O-Sulfates in Monkeys and Human Liver-Transplanted Chimeric Mice With or Without Bile Flow Diversion.

The present study examined the significance of enterohepatic circulation and the effect of rifampicin [an inhibitor of organic anion-transporting polypeptide 1B (OATP1B)] on the plasma concentrations of bile acid-O-sulfates (glycochenodeoxycholate-O-sulfate, lithocholate-O-sulfate, glycolithocholate-O-sulfate, and taurolithocholate-O-sulfate) in monkeys and human liver-transplanted chimeric mice (PXB mouse). Rifampicin significantly increased the area under the curve of bile acid-O-sulfates in monkeys (13-69 times) and PXB mice (13-25 times) without bile flow diversion. Bile flow diversion reduced the concentration of plasma bile acid-O-sulfates under control conditions in monkeys and the concentration of plasma glycochenodeoxycholate-O-sulfate in PXB mice.

Correction to: Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers.

There was a miscalculation of coproporphyrin I AUC in the published article (Volume 35, Number 7). After the correction of AUC, AUC ratio and R-square were re-calculated. Then, following corrections were made in the abstract, the body, Fig.

Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys.

Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed of a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species. Following intravenous (iv) administration of DS-8201a, the linker was stable in plasma, and systemic DXd exposure was low.

In vivo multiple metabolic pathways for a novel G protein-coupled receptor 119 agonist DS-8500a in rats: involvement of the 1,2,4-oxadiazole ring-opening reductive reaction in livers under anaerobic conditions.

A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. In vivo metabolic fates of [C]DS-8500a differently radiolabeled in the benzene ring or benzamide side carbon in rats were investigated. Differences in mass balances were observed, primarily because after the oxadiazole ring-opening and subsequent ring-cleavage small-molecule metabolites containing the benzene side were excreted in the urine, while those containing the benzamide side were excreted in the bile.

Interaction of Nevirapine with the Peptide Binding Groove of HLA-DRB1*01:01 and Its Effect on the Conformation of HLA-Peptide Complex.

Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its possible effect on the position and orientation of the ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide binding groove and the HA peptide stably binds on top of nevirapine at the groove.

Comparative Study of the Dose-Dependence of OATP1B Inhibition by Rifampicin Using Probe Drugs and Endogenous Substrates in Healthy Volunteers.

Purpose: To evaluate association of the dose-dependent effect of rifampicin, an OATP1B inhibitor, on the plasma concentration-time profiles among OATP1B substrates drugs and endogenous substrates.

Methods: Eight healthy volunteers received atorvastatin (1 mg), pitavastatin (0.2 mg), rosuvastatin (0.

Curcumin as an In Vivo Selective Intestinal Breast Cancer Resistance Protein Inhibitor in Cynomolgus Monkeys.

To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selective BCRP inhibition, in addition to several well known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole.

Investigation of Glycochenodeoxycholate Sulfate and Chenodeoxycholate Glucuronide as Surrogate Endogenous Probes for Drug Interaction Studies of OATP1B1 and OATP1B3 in Healthy Japanese Volunteers.

Purpose: To assess the use of glycochenodeoxycholate-3-sulfate (GCDCA-S) and chenodeoxycholate 3- or 24-glucuronide (CDCA-3G or -24G) as surrogate endogenous substrates in the investigation of drug interactions involving OATP1B1 and OATP1B3.

Methods: Uptake of GCDCA-S and CDCA-24G was examined in HEK293 cells transfected with cDNA for OATP1B1, OATP1B3, and NTCP and in cryopreserved human hepatocytes. Plasma concentrations of bile acids and their metabolites (GCDCA-S, CDCA-3G, and CDCA-24G) were determined by LC-MS/MS in eight healthy volunteers with or without administration of rifampicin (600 mg, po).

In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01.

Idiosyncratic ximelagatran-induced hepatotoxicity has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01 and ximelagatran has been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. In order to predict the possible interaction modes of ximelagatran with HLA-DR molecules, in silico docking simulations were performed. Molecular dynamics (MD) simulations were also performed to predict the effect of ximelagatran on the binding mode of the ligand peptide to HLA-DRB1*07:01.

Difference in Mechanism-Based Inhibition of Cytochrome P450 3A4 and 3A5 by a Series of Fluoroquinolone Antibacterial Agents.

A series of fluoroquinolone antibacterial compounds were found to be irreversible (compounds 1-5) and quasi-irreversible (compounds 6-9) inhibitors of CYP3A4. The purpose of this study was to evaluate their mechanism-based inhibition (MBI) potency against CYP3A5. Compounds 1-5 were also irreversible inhibitors of CYP3A5, whereas compounds 6-9 showed neither irreversible nor quasi-irreversible inhibition of CYP3A5.

Studies on novel HIF activators, A-503451sII: biological activities of A-503451A.

In the course of our screening, we discovered a novel compound, A-503451A, as a potent hypoxia-inducible factor (HIF) activator. In human hepatocarcinoma HepG2 cells, A-503451A induced HIF-mediated luciferase reporter gene expression and stabilized HIF-1α protein. A-503451A increased the mRNA expression levels and the protein secretion of HIF-dependent genes, vascular endothelial growth factor and erythropoietin.

Studies on novel HIF activators, A-503451s.I. Producing organism, fermentation, isolation and structural elucidation.

In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated.

Analysis of Mechanism-Based Inhibition of CYP 3A4 by a Series of Fluoroquinolone Antibacterial Agents.

A series of fluoroquinolone compounds (compounds 1-9), which contain a common quinolone scaffold, inactivated the metabolic activity of CYP3A. The purpose of this study was to identify mechanism-based inhibition (MBI) among these fluoroquinolone compounds by metabolite profiling to elucidate the association of the substructure and MBI potential. Reversibility of MBI after incubation with potassium ferricyanide differed among the test compounds.

Identification and biological activity of ogipeptins, novel LPS inhibitors produced by marine bacterium.

A library of secondary metabolites from microorganisms was screened to identify novel inhibitors against lipopolysaccharide (LPS), a strong stimulant of innate immunity. Novel cyclic peptides, ogipeptin A, B, C and D, were identified in the culture broth of the marine bacterium Pseudoalteromonas sp. SANK 71903.

Ogipeptins, novel inhibitors of LPS: physicochemical properties and structural elucidation.

In the course of our screening program for inhibitors of lipopolysaccharide binding to cellular receptor CD14, a potent inhibitory activity was detected in the cultured broth of Pseudoalteromonas sp. SANK 71903. Four active compounds, ogipeptins A, B, C and D, were isolated from the cultured broth.

IQGAP1 selectively interacts with K-Ras but not with H-Ras and modulates K-Ras function.

K-Ras is frequently mutated and activated especially in pancreatic cancers. To analyze K-Ras function, we have searched for K-Ras interacting proteins and found IQ motif containing GTPase activating protein 1 (IQGAP1) as a novel K-Ras binding protein. IQGAP1 has been known as a scaffold protein for B-Raf, MEK1/2 and ERK1/2.

Pedopeptins, novel inhibitors of LPS: taxonomy of producing organism, fermentation, isolation, physicochemical properties and structural elucidation.

In the course of our screening for inhibitors of lipopolysaccharide (LPS) binding to cellular receptor CD14, potent inhibitory activity was detected in the cultured broth of Pedobacter sp. SANK 72003. Three active compounds, pedopeptin A, B and C, were isolated from the broth and their structures were elucidated by physicochemical and spectral data to be new cyclic depsipeptides.

Screening and biological activities of pedopeptins, novel inhibitors of LPS produced by soil bacteria.

Lipopolysaccharide (LPS) is a strong endotoxin and is delivered to the cell surface signaling receptor, Toll-like receptor 4 and MD-2 complex, via soluble cluster of differentiation (CD) 14 or membranous CD14, resulting in the induction of the inflammatory response. To obtain new compounds that block LPS binding to CD14, we designed a high-throughput screening based on time-resolved intermolecular fluorescence resonance energy transfer. This cell-free screening system successfully led to the discovery of novel inhibitors of LPS-CD14 interaction from the library of the secondary metabolites of microorganisms.

A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1.

The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4.

IDH1 and IDH2 have critical roles in 2-hydroxyglutarate production in D-2-hydroxyglutarate dehydrogenase depleted cells.

D-2-hydroxyglutaric aciduria (D-2HGA) is a hereditary metabolic disorder characterized by the elevated levels of D-2-hydroxyglutaric acid (D-2HG) in urine, plasma and cerebrospinal fluid. About half of the patients have autosomal recessive mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene. To analyze the origin of D-2HG in D2HGDH-depleted cells, we used small interfering RNA (siRNA) techniques.

Structural basis of digoxin that antagonizes RORgamma t receptor activity and suppresses Th17 cell differentiation and interleukin (IL)-17 production.

The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation.

Long-term effects of the trehalase inhibitor trehazolin on trehalase activity in locust flight muscle.

Trehalase (EC 3.2.1.