Pharmacokinetic Study In Rats Research Articles

Study on the Absorption of Arsenic Species in Realgar Based on the Form and Valence.

At present, several experiments have been carried out to study the changes in total arsenic content of realgar and its prescription, but few researches on its form and valence. We evaluated the change in arsenic species concentration in realgar from the perspective of absorption by using an in vitro dissolution study, an in vivo unidirectional intestinal perfusion study, transmembrane transport in Caco-2 cells, and a pharmacokinetic study in rats. In the gastrointestinal tract, arsenic species are mainly present inorganic forms of AsIII and AsV. The cumulative dissolution rates of soluble arsenic in 4 h artificial gastric fluid and 8 h artificial intestinal fluid were 21.99% and 59.20%, respectively. The Papp values of soluble arsenic in realgar in the duodenum, jejunum, and ileum of rats were 5.4 × 10−3, 6.1 × 10−3 and 5.8 × 10−3 cm/min, respectively. In the process of small intestine perfusion, the AsIII of realgar was partially converted into AsV in the duodenum and jejunum. As the transport time increased, the transmembrane transport rate and Papp value of soluble arsenic in realgar were increased in Caco-2 cells, and it also suggested that arsenic species may be passively transported across the Caco-2 cell monolayer. The Cmax and AUC (0-24) of AsIII, AsV, and DMA in plasma of realgar were 41.26 ng L−1/343.977 ng h mL−1, 21.626 ng L−1/47.310 ng h mL−1, and 2.372 ng L−1/30.429 ng h mL−1, respectively. Tmax and MRT (0-∞) of AsIII, AsV, and DMA were 2.571 h/9.649 h, 0.393 h/2.790 h, and 3.143 h/23.145 h, respectively. It is hoped to provide a basis for clarifying the arsenic species in realgar.

Development, evaluation, pharmacokinetic and biodistribution estimation of resveratrol-loaded solid lipid nanoparticles for prostate cancer targeting

Background and aim The study was to extend systemic circulation and biological half-life (t1/2) of trans-resveratrol (RSV) using solid lipid nanoparticles (RSV-SLN) to improve its anti-cancer potential. Methods RSV-SLN was prepared by solvent emulsification evaporation technique and proceeded for evaluation like particle size, PDI, zeta potential, in vitro release, in vitro cytotoxicity, cellular internalisation, haemolysis and erythrocyte membrane integrity, platelet aggregation and pharmacokinetic studies in rats. Moreover, cancer cells accumulation of RSV-SLN also needs to be evaluated for proving their targeting ability. Result Prepared SLN showed 126.85 ± 12.09 nm particle size, −24.23 ± 3.27 mV Zeta potential and 74.67 ± 4.76%. release at 48 h and haemocompatible. The cellular internalisation image showed the SLN reach in a cytoplasm and nucleus of PC3 prostate cells. RSV-SLN exhibited high t1/2 (8.22 ± 1.36 h) and 7.19 ± 0.69 h MRT (Mean residence time) and lower clearance i.e. 286.42 ± 13.64 mL/min/kg. The bio-distribution of RSV-SLN was found to be extremely high in prostate cells and accumulate 7.56 times greater than that of RSV solution. Conclusion The developed RSV-SLN can be applied as potential carrier for delivery of drug of chemotherapeutics at an extend systemic circulation and targeting efficiency at tumour site.

RP-HPLC method development, validation and pharmacokinetic applicability in preclinical evaluation of rhein treated with novel diacerein eutectics.

The current study represents a bioanalytical method for the estimation of rhein (Rh, an active metabolite of diacerein, DIA) in rats treated with novel DIA eutectics to investigate the pharmacokinetics of DIA. A simple protein precipitation technique was used to extract Rh and the internal standard (IS), p-aminobenzoic acid, injected into a Phenomenex Gemini C18 column. The separation was achieved by a gradient elution comprising ammonium acetate (10mm; pH3.0) and acetonitrile in an 18 min run time at a flow rate of 0.8ml/min with retention times of 11.8min (Rh) and 5.9min (IS). The results revealed that the proposed method is linear over a range of 200-20,000 ng/ml (r2 > 0.9988) of Rh and is precise and accurate. The method was fully validated as per the US Food and Drug Administration guidelines and a pharmacokinetic study in rats was performed for Rh following oral administration of the pure DIA and newly developed eutectics. Therefore, the present method could be used to estimate DIA to illustrate a comparative pharmacokinetic analysis. This can also be applied to its related multicomponent formulations for future studies.

Co-amorphous systems using epigallocatechin-3-gallate as a co-former: Stability, in vitro dissolution, in vivo bioavailability and underlying molecular mechanisms

Co-amorphous strategy has been extensively investigated to improve the dissolution of hydrophobic drugs. Here, epigallocatechin-3-gallate (EGCG) was exploited as a co-former in co-amorphous systems based on its unique structure including phenyl rings, phenolic hydroxyl groups and the galloyl moiety. Two model BCS class II drugs, simvastatin (SIM) and nifedipine (NIF), were selected to be co-amorphized with EGCG. All drug-EGCG systems at three molar ratios became amorphous by the means of spray drying and showed high physically stable either under dry condition and 75 % RH at 40 °C or under dry conditions at 25 °C. The optimal feed molar ratios of both EGCG based co-amorphous systems fabricated were determined to be three, under which the significant increases were obtained in the maximum apparent concentrations of 4.90-fold for SIM at 1 h and 106.03-fold for NIF at 0.25 h compared to crystalline drugs by non-sink dissolution studies. The underlying molecular mechanisms of two co-amorphous systems formation were involved in molecular miscibility, hydrogen bonds and π-π stacking interactions unraveled by means of DSC, FTIR and molecular dynamics simulations. More to the point, oral pharmacokinetic studies in rats demonstrated that co-amorphous SIM-EGCG and NIF-EGCG systems at 1:3 have a significant increase in Cmax of 1.81- and 5.69-fold, and AUC 0-24h of 1.62- and 4.57-fold compared with those of corresponding crystalline drugs, respectively. In conclusion, EGCG is proved to be a promising co-former in co-amorphous systems.

Novel difluoromethylated 1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6 receptor antagonist with AMDE-improving properties: Design, synthesis, and biological evaluation

Serotonin type 6 receptor (5-HT6R) has been considered as a particularly promising target for treating cognitive deficits due to the positive effects of its antagonists in a wide range of memory impairment paradigms. In this study, we designed, synthesized, and evaluated a series of 3-(difluoromethyl)-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole derivatives as potent 5-HT6R antagonists. Structure-activity relationship study led to the discovery of five compounds (6a, 6m, 6n, 6p and 6q) with potent binding affinity at 5-HT6R. In in vivo pharmacokinetic studies in rats, 6p showed 30-folds higher AUC (267 ng·h/mL) and better bioavailability (34.39 %) than those of 6a (9.37 ng·h/mL and 5.95 %, respectively) by using difluoromethyl group replacing a methyl group. Besides, 6p showed good brain penetration with Cb/Cp ratio ∼6. Based on the pharmacological characteristics and favorable pharmacokinetic properties, 6p was further chosen to evaluate cognition-enhancing property in the preliminary in vivo models. It is identified that 6p not only prevented scopolamine-induced learning deficits in the novel object recognition test but also rescued the recognition barrier caused by scopolamine. Finally, the combination of 6p and donepezil produces synergistic effects on increasing the acetylcholine levels in the intracerebral hippocampus. In light of these findings, we propose 6p as a potential 5-HT6R antagonist for treatment of AD.

Optimized self-microemulsifying drug delivery system improves the oral bioavailability and brain delivery of coenzyme Q10

Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q10, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q10 solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q10 within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q10 suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q10 suspension. A Coenzyme Q10 brain distribution study revealed a higher Coenzyme Q10 distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q10 suspension. Coenzyme Q10-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q10.

Discovery, Optimization, and Evaluation of Potent and Selective PI3Kδ-γ Dual Inhibitors for the Treatment of B-cell Malignancies.

Nowadays, PI3Kδ-γ dual inhibitors have been approved for the treatment of B-cell malignancies. Dual inhibition of PI3Kδ and PI3Kγ represents a unique therapeutic opportunity and may confer greater benefits than either isoform inhibition alone in the management of hematological malignancies. However, currently available dual inhibitors of PI3Kδ-γ compromise in at least one of several essential properties in terms of potency, selectivity, and pharmacokinetic (PK) profiles. Hence, the main challenge of our optimization campaign was to identify an oral available PI3Kδ-γ dual inhibitor with an optimum balance of potency, selectivity, and PK profiles. The medicinal chemistry efforts culminated in the discovery of compound 58, which exhibited strong potency and high selectivity along with excellent in vivo profiles as demonstrated through PK studies in rats and through pharmacodynamic studies in an SUDHL-6 xenograft model. All the results suggest that compound 58 may be a promising candidate for the treatment of B-cell malignancies.

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs.

A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing.

Enantioseparation and determination of oxypeucedanin and its application to a stereoselective analysis in Angelica Dahuricae Radix and pharmacokinetic study of rats

In this study, a new enantioseparation method was established for the quantitative analysis of the oxypeucedanin enantiomers by using cellulose tris(3,5-dichlorophenyl carbamate) stationary phase column Chiralpak IC. For this method, enantiomeric separation of oxypeucedanin was achieved with the mobile phase consisting of acetonitrile-water (60:40, v/v) at a flow rate of 0.5 mL/min by changing the type and proportion of mobile phase. And the quantitative determination of racemic oxypeucedanin in Angelica Dahuricae Radix (in vitro) and rat plasma (in vivo) were performed on above-mentioned condition by High PerformanceLiquid Chromatography combined with diode arrangement detector (HPLC-DAD) and mass spectrometry (HPLC-MS/MS). The precision, repeatability, stability, recovery were within the acceptance criteria. And the method was validated in the concentration range of 1-400 μg/mL for the two enantiomers in vitro and 0.2–600 ng/mL in vivo. After validation, the established method was successfully applied to the stereoselective analysis of racemic oxypeucedanin in Angelica dahurica from different regions and the stereoselective pharmacokinetic investigation in rat. Results showed that the (+)-oxypeucedanin was at a relative high level in Angelica dahuricae Radix and (−)-oxypeucedanin performed a higher plasma concentration, which demonstrated the difference of oxypeucedanin enantiomers both in vitro and in vivo.

UPLC-MS/MS Assay for Quantification of Wedelolactone and Demethylwedelolactone in Rat Plasma and the Application to a Preclinical Pharmacokinetic Study.

Wedelolactone and demethylwedelolactone are the two major coumarin constituents of Herba Ecliptae. The objective of this work was to develop and validate a sensitive, rapid, and robust UPLC-MS/MS method for the simultaneous quantification of wedelolactone and demethylwedelolactone in rat plasma. Wedelolactone and demethylwedelolactone were extracted from rat plasma by protein precipitation with acetonitrile. Electrospray ionization in negative mode and selected reaction monitoring (SRM) were used for wedelolactone and demethylwedelolactone at the transitions m/z 312.8→298.0 and m/z 299.1→270.6, respectively. Chromatographic separation was conducted on a Venusil C18 column (50 mm × 2.1 mm, 5 μm) with isocratic elution of acetonitrile-0.1% formic acid in water (55:45, v/v) at a flow rate of 0.3 mL/min. A linear range was observed over the concentration range of 0.25-100 ng/mL for wedelolactone and demethylwedelolactone. They reached their maximum plasma concentrations (Cmax, 74.9±13.4 ng/mL for wedelolactone and 41.3±9.57 ng/mL for demethylwedelolactone) at the peak time (Tmax) of 0.633 h and 0.800 h, respectively. The AUC0-t value of wedelolactone (260.8±141.8 ng h/mL) was higher than that of demethylwedelolactone (127.4±52.7 ng h/mL) by approximately 2-fold, whereas the terminal elimination half-life (t1/2) of wedelolactone (2.20±0.59 h) showed the approximately same as that of demethylwedelolactone (2.08±0.69 h). Based on full validation according to US FDA guidelines, this UPLC-MS/MS method was successfully applied to a pharmacokinetic study in rats.

Abstract 3346: BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC

Abstract Background: Activating mutations in EGFR, e.g., L858R (L) and Del19 (D), are observed in 14.1-32.3% of NSCLC worldwide and defines a druggable entity. Single agent EGFR TKI treatment was established in clinical trials. However, a treatment-emergent mutation of T790M (T) was identified as a major source of drug resistance. Irreversible 2nd and 3rd generation EGFR TKIs were shown effective. Mutant-specific inhibition by 3rd generation EGFR TKIs reduced adverse events such as skin toxicities. The emergence of a missense mutation at C797 (C), to which irreversible TKIs covalently bind, limited their efficacy. Patients harboring treatment-emergent C mutations are left with few therapeutic options. Despite anecdotal reports of efficacy from 1st generation TKIs, these complex molecular variants involving C797 are an increasing clinical concern. To prevent the emergence of drug-resistant subclones, a broad-spectrum EGFR TKI against both treatment-emergent and drug-naïve mutants is required. Such a 4th generation EGFR TKI must also enable monotherapy, allowing precise dose adjustment in case of toxicity. Method: Derived from BBT-176 which is under clinical evaluation (NCT04820023), we synthesized BBT-207 and other related molecules. Using Promega ADP-Glo™ kinase assay, we tested compounds against wild-type (WT) and mutated EGFR proteins. Ba/F3 cells harboring WT and mutated EGFR genes were created and cell viability was measured by CellTiter-Glo® and SpectraMax iD3®. In vivo anti-tumor activity was evaluated in Ba/F3 cell-derived xenograft models and an Osimertinib-resistant patient-derived xenograft model. Single dose pharmacokinetic (PK) study was performed in animals. Results: BBT-207 showed IC50 values < 10 nM against EGFR triple mutants (DTC and LTC) and comparable IC50 values against double mutants (DC and LC), while Osimertinib was ineffective in both groups. BBT-207 was also as active as Gefitinib to single mutants (D and L). Double mutants containing T790M (DT and LT) were inhibited effectively by BBT-207 and Osimertinib at similar concentrations, while not by Gefitinib. In in vivo models to which Osimertinib was inactive (LC and DTC), significant tumor growth inhibition was observed from BBT-207 alone, which was enhanced by the addition of Osimertinib. PK studies in mouse, rat, dog and monkey were consistent with high exposure and sustained drug concentrations above the IC50 values, with evidence of penetration into the central nervous system. Conclusion: BBT-207 is a reversible, mutant-specific, broad-spectrum TKI, active to clinically observed mutations of EGFR and is expected to be compatible with monotherapy of QD schedule in humans. BBT-207 is well-positioned to augment the treatment of EGFR mutated NSCLC, either for acquired drug resistance or in earlier line. Citation Format: Taiguang Jimmy Jin, Sang-Uk Kang, Chulwon Kim, Jehrod Brenneman, Mihee Song, Pavel Printsev, Bo-Bae Seo, Yong-Hee Lee, Sang-Yoon Lee. BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3346.

JBP485, A Dual Inhibitor of Organic Anion Transporters (OATs) and Renal Dehydropeptidase-I (DHP-I), Protects Against Imipenem-Induced Nephrotoxicity.

Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP’s plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC50 value of 12.15 ± 1.22 μM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting.

Synthesis and Anti-Neuroinflammatory Activity of 1,7-diphenyl-1,4-heptadien-3-ones in LPS-Stimulated BV2 Microglia Via Inhibiting NF-κB/MAPK Signaling Pathways.

A series of 1,7-diphenyl-1,4-heptadien-3-ones with various substituents (HO-, CH3O-, CH3-, Cl-) on the phenyl rings were synthesized and evaluated for anti-neuroinflammatory effects in LPS-stimulated BV2 microglia. The pharmacological results showed that the target compounds bearing methoxy groups greatly inhibited LPS-induced NO release, and that the active compounds CU-19 and CU-21 reduced the level of NO, TNF-α, IL-6 and PGE-2, downregulated the expression of COX-2 and iNOS in LPS-stimulated BV2 cells. A study of the mechanism of action revealed that CU-19 and CU-21 inhibited the nuclear translocation of NF-κB and phosphorylation of MAPKs (ERK, JNK, and p38). A preliminary pharmacokinetic study in rats revealed that the pharmacokinetic properties of CU-19 and CU-21 were dramatically ameliorated in comparison with the pharmacokinetic properties of curcumin.

Intranasal Delivery of Darunavir-Loaded Mucoadhesive In Situ Gel: Experimental Design, In Vitro Evaluation, and Pharmacokinetic Studies.

The clinical efficacy of antiretroviral therapy in NeuroAIDS is primarily limited by the low perfusion of the drug to the brain. The objective of the current investigation was to design and develop an in situ mucoadhesive gel loaded with darunavir to assess the feasibility of brain targeting through the intranasal route. Preliminary batches (F1–F9) were prepared and evaluated for various pharmaceutical characteristics. A full factorial design of the experiment was applied to optimize and assess the effect of two influencing variables (Carbopol 934P (X1) and Poloxamer 407 (X2)) on the response effects (gelation temperature (Y1) and % drug release (Y2) at 8 h). The data demonstrate that both influencing variables affect the response variables significantly (p < 0.05). The optimized formulation (F7) exhibited favorable rheological properties, adequate mucoadhesion, sustained drug release, and greater permeation across the nasal mucosa. An in vitro ciliotoxicity study confirms the nontoxicity of the optimized in situ gel (D7) on the nasal mucosa. An in vivo pharmacokinetic study in rats was performed to assess drug targeting to the brain following the nasal application of the selected in situ gel (D7). Significantly higher (p < 0.0001) Cmax (~4-fold) and AUC0-α (~3.5-fold) values were noticed in the brain after nasal application, as compared to the intravenous route. However, less systemic exposure to darunavir was noticed with nasal therapy, which confirms the low absorption of the drug into the central compartment. Overall, the data here demonstrate that the optimized in situ mucoadhesive nasal gel is effective in targeting darunavir to the brain by the nasal route and could be a viable option for the treatment of NeuroAIDS.

Beneficial herb-drug interaction of Gnaphalium affine extract on benzbromarone: A pharmacokinetic and pharmacodynamic study in rats

BackgroundGnaphalium affine D. Don extract (GAD) enhanced efficacy and reduced toxicity of benzbromarone (BBR) in combination use. However, little is known about effects of GAD on the pharmacokinetics (PKs) and metabolic enzymes of BBR. PurposeTo investigate the pharmacokinetic (PK) and pharmacodynamic (PD) mechanism of the herb-drug interactions (HDIs) between GAD and BBR. Study design and methodsIntragastric single BBR (4.5 or 50 mg/kg), single BBR (4.5 or 50 mg/kg) + single GAD (450 mg/kg, 2 h after BBR-administration), or single BBR (4.5 or 50 mg/kg) + multiple GAD (450 mg/kg/day, once daily for 7 days) were administered to both sexes for BBR PK studies in normal rats. Intragastric multiple BBR (4.5 mg/kg/day), or multiple BBR (4.5 mg/kg/day) + multiple GAD (450 mg/kg/day, 2 h after BBR-administration) were administered for BBR PK and PD studies in male rats with hyperuricemic nephropathy (HN). The cumulative anti-hyperuricemic effects of BBR and BBR+GAD were determined by plasma uric acid (UA) concentration-time curve and area under curve (AUCUA). An in vivo cocktail approach was employed to determine the effects of GAD on cytochrome P450 (CYP) 2C11(9) and 1A2 – mediated drug metabolism. ResultsIn normal rats, the repeated dose administration of GAD induced a significant increase of BBR AUC and prolonged the mean residence time (MRT) (p < 0.05). systemic exposure to BBR and metabolically derived hydroxybenzbromarones was significantly greater in female compared with male rats (p < 0.05). In HN rats, post-administration of GAD resulted in significantly higher bioavailability and enterohepatic recycling (ER) of BBR relative to the BBR alone administrated group from the prolongation of terminal elimination half-life (T1/2) and MRT of BBR (p < 0.05). Significantly higher urate-lowering effect of BBR+GAD compared with BBR alone was generally observed at post-dosing most time points with a maximal effect of 84.3% (acute treatment), 71.4% (7-day subchronic treatment) and 82.5% (14-day subchronic treatment) reduction in UA levels. Additionally, GAD showed a significant inhibitory effect on CYP2C11(9)-mediated tolbutamide (probe substrate) metabolism with ≥ 1.25 but < 2-fold increase in AUCtolbutamide. ConclusionsPD synergism demonstrated with the BBR+GAD combination could be explained by the PK interaction observed partially from CYP2C11(9)-mediation and enterohepatic recycling.

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid β Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease.

Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients’ brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.

Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of HIV-1 allosteric integrase inhibitors

Allosteric integrase inhibitors (ALLINIs) of HIV-1 may hold promise as a novel mechanism for HIV therapeutics and cure. Scaffold modifications to the 4-(4,4-dimethylpiperidinyl) 2,6-dimethylpyridinyl class of ALLINIs provided a series of potent compounds with differentiated 5/6 fused ring systems. Notably, inhibitors containing the 1,2,4-triazolopyridine and imidazopyridine core exhibited single digit nM antiviral potency and low to moderate clearance after intravenous (IV) dosing in rat pharmacokinetic (PK) studies. The 1,2,4-triazolopyridines showed a higher oral exposure when compared to the imidazopyridines. Further modifications to the C5 substituent of the 1,2,4-triazolopyridines resulted in a new lead compound, which had improved rat IV/PO PK compared to the former lead compound GSK3739936, while maintaining antiviral potency. Structure-activity relationships (SAR) and rat pharmacokinetic profiles of this series are discussed.

Excipient-free nanodispersions dominated by amphiphilic glycosides for bioavailability enhancement of hydrophobic aglycones, a case of glycyrrhetinic acid with diammonium glycyrrhizinate

Natural aglycones, a major ingredient accompanied by glycosides in plants, have played an important role in the treatment of various diseases. However, their bioavailability is limited by their poor water solubility. In contrast to previous efforts that required the use of new exotic materials which may raise concerns about biocompatibility, we report the first case of excipient-free nanodispersions in which an insoluble glycyrrhetinic acid (GA) assembled with its amphiphilic parent drug diammonium glycyrrhizinate (DG) into water-dispersible nanodispersions (130.8 nm for particle size and 91.74% for encapsulation efficiency). This strategy largely increased GA's water apparent solubility by hundreds of times to 549.0 μg/mL with a high cumulative dissolution percentage in vitro greater than 80% in 5 min. The study on the formation mechanism showed that the OH, C-O and C=O group stretching peaks shifted in the FTIR spectra of GA-DG nanodispersions, while the COOH peak (δ COOH 12.19 ppm) disappeared in the 1H NMR spectrum of GA-DG nanodispersions, indicating that carboxyl groups on GA may interact with the hydroxyl groups of DG in solution. Molecular dynamics simulations suggested that both hydrophobic interactions and hydrogen-bond interactions contribute to the coassembly of GA and DG molecules in aqueous solution. Oral pharmacokinetic studies in rats demonstrated that such nanodispersions have a significant increase in Cmax and AUC0-t of 2.45- and 3.45-fold compared with those for GA, respectively. Therefore, this strategy, employing amphiphilic glycosides as excipients to prepare nanodispersions, not using new materials, paves the way for the further application of hydrophobic aglycone drugs.

Phenoxyaromatic Acid Analogues as Novel Radiotherapy Sensitizers: Design, Synthesis and Biological Evaluation

Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds 19c (∆P50 = 45.50 mmHg) and 19t (∆P50 = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P50 = 36.40 mmHg). Preliminary safety evaluation revealed that 19c exhibited no cytotoxicity towards HEK293 and U87MG cells, while 19t was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that 19c exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that 19c was orally available.

A Simple and Sensitive HPLC-MS/MS Assay for the Quantitation of Blonanserin and N-Desethyl Blonanserin in Rat Plasma and Its Application to Pharmacokinetic Study.

A high-performance liquid chromatographic method coupled with triple quadrupole mass spectrometry (LC-MS/MS) for the analysis of blonanserin and its active metabolite, N-desethyl blonanserin, in rat plasma has been developed and validated. The biological samples were treated by simple direct protein precipitation before separation on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 μm) with a column temperature of 35°C at a flow rate of 0.5 mL/min. The mobile phase A is a mixture of methanol and water (75 : 25, v/v, 5 mM ammonium formate), and the mobile phase B is acetonitrile containing 0.1% formic acid. The ratio of mobile phase A to mobile phase B is 15 : 85. Electrospray ionization (ESI) multiple reaction monitoring modes are used for detection, which are m/z 368.10 ⟶ 296.90 (blonanserin), m/z 340.15 ⟶ 297.05(N-desethyl blonanserin), and m/z 348.15⟶ 302.05 (N-desethyl blonanserin-d8). The linear response range was 0.1–100.0 ng/mL for blonanserin and N-desethyl blonanserin. The lower limit of quantification (LLOQ), calibration curves, carryover, and matrix effects were sufficiently accurate and precise according to the National Medical Products Administration (NMPA) guidelines for bioanalytical method validation. This analytical method was successfully applied in a blonanserin-poloxamer thermosensitive gel pharmacokinetic study in rats.