Pharmacokinetics and Safety Evaluation of Single-Dose Saroglitazar Magnesium in Subjects with Hepatic Impairment.

Saroglitazar magnesium, a dual peroxisome proliferator-activated receptor agonist, is under evaluation for treating various liver conditions. While the pharmacokinetics (PK) of saroglitazar have been extensively studied in diverse preclinical models and healthy subjects, a comprehensive assessment of its PK behavior under conditions of hepatic impairment is lacking. In this Phase 1, open-label, parallel-group study, the PK of a single dose of 4-mg saroglitazar magnesium was investigated in subjects having varying degrees of hepatic impairment with and without portal hypertension compared with appropriately matched individuals having normal hepatic function. Treatment-emergent adverse events for safety were also evaluated. Thirty-two subjects were enrolled in the hepatic-impaired groups and 23 subjects in the normal hepatic function group. Mild and moderate hepatic impairment did not significantly affect the PK of saroglitazar, compared with normal hepatic function. Although severe hepatic impairment did not alter maximum observed plasma concentration and half-life; saroglitazar exposure (area under the plasma concentration-time curve from time 0 to infinity) increased 3-fold, while the clearance was 61% lower compared to the subjects with normal hepatic function. This may require close monitoring or dose adjustments in individuals with severe hepatic impairment. A single oral dose of saroglitazar magnesium 4 mg was found to be safe and well tolerated in subjects with varying degrees of hepatic function.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling), first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH.

Evaluation of herb-drug interaction of ambrisentan with shikonin based on UPLC-MS/MS.

CONTEXT: Ambrisentan is an oral endothelin-receptor antagonist (ERA). However, there is no report on the interaction between ambrisentan and shikonin. OBJECTIVE: To investigate the effect of shikonin on ambrisentan metabolism in vivo and in vitro. MATERIALS AND METHODS: This study developed an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for simultaneous determination of ambrisentan and (S)-4-hydroxymethyl ambrisentan in rat plasma. Twelve male Sprague-Dawley (SD) rats were divided into two groups (n = 6): the control group and shikonin (20 mg/kg) group. The pharmacokinetics of ambrisentan (2.5 mg/kg) were investigated after 30 min. Additionally, human and rat liver microsomes were used to investigate the herb-drug interaction. RESULTS: The UPLC-MS/MS method was shown to be accurate, precise and reliable, and was successfully applied to the herb-drug interaction study of ambrisentan with shikonin. When co-administrated with 20 mg/kg shikonin, the Cmax and AUC(0-∞) of ambrisentan were significantly increased by 44.96 and 16.65%, respectively (p < 0.05). In addition, there were modest decreases in (S)-4-hydroxymethyl ambrisentan Cmax and AUC(0-∞) in the presence of shikonin (p < 0.05), which indicated that these results were in accordance with the inhibition of shikonin on ambrisentan metabolism. Moreover, enzyme kinetic study indicated that shikonin had an inhibitory effect on human and rat microsomes where the IC50 values of shikonin were 5.865 and 6.358 µM, respectively. CONCLUSIONS: Our study indicated that shikonin could inhibit ambrisentan metabolism. Further studies need to be carried out to verify whether similar interaction truly apply in humans and whether this interaction has clinical significance.

Development of omega-3 loxoprofen-loaded nanoemulsion to limit the side effect associated with NSAIDs in treatment of tooth pain.

The majority of newly developed drugs need to be incorporated with delivery systems to maximize their effect and minimize side effects. Nanoemulsions (NEs) are one type of delivery system that helps to improve the solubility and dissolution of drugs, attempting to enhance their bioavailability and onset of action. The objective of this investigation was to develop an omega-3 oil-based NE loaded with loxoprofen (LXP) to enhance its dissolution, in vitro release, and mucosal penetration and decrease its mucosal ulcerative effects when applied in an oral treatment. LXP-loaded NEs were formulated with varying levels of omega-3 oil (10-30%), surfactant polyoxyethylene-C21-ethers (laureth-21) (40-60%), and co-surfactant polyethylene glycol-40 hydrogenated castor oil (HCO-40) (30-50%) using an extreme vertices mixture design. The developed NEs were characterized for globule size and drug loading capacity. The optimal formulation was tested for in vitro drug release, ex vivo permeation, and ulcer index value. The developed NE acquired a globule size ranging 71-195 nm and drug loading capacity of 43-87%. Considering the results of the in vitro release study, the optimized NE formulation achieved 2.45-fold and 2-fold increases in drug permeation across tested mucosa compared to a marketed tablet and drug aqueous dispersion, respectively. Moreover, the optimum NE exhibited the best ulcer index in comparison to drug aqueous suspension and different formulations when tested in rats. Overall, this research highlights the capacity of NEs to deliver LXP with enhanced solubility, drug release, and permeation while effectively protecting the application site from side effects of the model drug.

Artepillin C: A comprehensive review of its chemistry, bioavailability, and pharmacological properties.

Artepillin C (ARC), a prenylated derivative of p-coumaric acid, is one of the major phenolic compounds found in Brazilian green propolis (BGP) and its botanical source Baccharis dracunculifolia. Numerous studies on ARC show that its beneficial health effects correlate with the health effects of both BGP and B. dracunculifolia. Its wide range of pharmacological benefits include antioxidant, antimicrobial, anti-inflammatory, anti-diabetic, neuroprotective, gastroprotective, immunomodulatory, and anti-cancer effects. Most studies have focused on anti-oxidation, inflammation, diabetic, and cancers using both in vitro and in vivo approaches. Mechanisms underlying anti-cancer properties of ARC are apoptosis induction, cell cycle arrest, and the inhibition of p21-activated kinase 1 (PAK1), a protein characterized in many human diseases/disorders including COVID-19 infection. Therefore, further pre-clinical and clinical studies with ARC are necessary to explore its potential as intervention for a wide variety of diseases including the recent pandemic coronaviral infection. This review summarizes the comprehensive data on the pharmacological effects of ARC and could be a guideline for its future study and therapeutic usage.

Bioequivalence and Tolerability of Ambrisentan: A Pharmacokinetic Study in Mexican Healthy Male Subjects.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive rise in pulmonary vascular resistance. Ambrisentan is an oral, propanoic acid based-endothelin receptor antagonist (ERA), selective for the endothelin type-A receptor, which is approved for the treatment of PAH. The Colombia National Food and Drug Surveillance Institute regulatory criteria require demonstrating that the proposed generic product is bioequivalent to its reference-listed drug to obtain marketing approval. OBJECTIVES: The purpose of this study was to test the bioequivalence, pharmacokinetics, and tolerability of ambrisentan 10 mg tablets. METHODS: In this open-label, randomized, oral single-dose, two-way crossover bioequivalence study, 26 Mexican adult healthy male subjects received either the generic product of ambrisentan 10 mg or the reference product Volibris® (ambrisentan) 10 mg tablets during each study period under fasting conditions. There was a 7-day washout period between each dosing. Ambrisentan concentrations in plasma samples were quantified using a validated ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method. Blood samples were collected up to 72 h post-dose in each study period. The primary end points were maximum plasma concentration (Cmax) and area under the plasma concentration-time (AUC0-t) curve between 0 and 72 h for ambrisentan. RESULTS: The ratios (90% CI) of geometric mean for ambrisentan were 104.3% (97.12-111.98%) and 100.2% (95.56-104.72%). These pharmacokinetic parameter values lie within the INVIMA-specified bioequivalence limits of 80%-125%. Nervous system disorders were the most common adverse events (AEs). All AEs were mild to moderate in nature and were resolved after follow-up or pharmacologic treatment. Both products were safe and well tolerated. CONCLUSIONS: The test product ambrisentan 10 mg tablets is bioequivalent to the reference product Volibris® (ambrisentan) 10 mg tablets. Both treatments were well tolerated in the Mexican male population of this study. TRIAL REGISTRATION: COFEPRIS National Clinical Trials Registry number 183300410B0367/2018.

Simultaneous determination of TUG-891 and its metabolites in rat plasma using LC-HRMS with application to preclinical pharmacokinetic study.

In this study, a simple and reliable LC-MS/MS method was first proposed for the simultaneous determination of TUG-891 and its metabolites TUG-891-alcohol, TUG-891-aldehyde, and TUG-891-acid in rat plasma. The analytes and fasiglifam (internal standard) were extracted from plasma samples with acetonitrile and separated using an Acquity BEH C18 column (1.7 µm, 2.1 × 50 mm) with water containing 0.05% ammonium hydroxide and acetonitrile containing 0.05% ammonium hydroxide as the mobile phase. A Q-Exactive Orbitrap mass spectrometer in full-scan mode was used for mass detection, and the data analysis was obtained using a mass extraction window of 5 ppm. The calibration curves exhibited excellent linearity (correlation coefficient > 0.9981) in the concentration range of 0.5-1000 ng/mL. The lower limit of quantification was 0.5 ng/mL for all analytes. The intra- and inter-day precision was less than 11.31%, and the accuracy ranged from -11.50 to 9.50%. The extraction recovery of the analytes from rat plasma was greater than 82.31%, and no obvious matrix effect was found. The established method was further applied to the pharmacokinetic study of TUG-891, TUG-891-alcohol, TUG-891-aldehyde, and TUG-891-acid in rat after a single dose of 5-mg/kg treatment of TUG-891. The results demonstrated that TUG-891 was rapidly metabolized into its metabolites and the systemic exposures of the metabolites were much higher than those of TUG-891.

Fast off-line FPSE-HPLC-PDA determination of six NSAIDs in saliva samples.

A fast off-line FPSE-HPLC-PDA method has been reported that allows simultaneous clean up and determination of six non-steroidal anti-inflammatory drugs (NSAIDs) in saliva samples from healthy volunteers. Particularly, furprofen, indoprofen, ketoprofen, fenbufen, flurbiprofen, and ibuprofen were chromatographically resolved. Benzyl paraben was chosen as the internal standard (BzPB, IS). These target compounds were successfully extracted from human saliva using fabric phase sorptive extraction (FPSE) and then analysed in the liquid chromatographic system by means of a short analytical column (Symmetry C18, 75 × 4.6 mm, 3.5 µm) using acetonitrile (AcN) and phosphate buffer (PBS, 30 mM; pH = 2.5) as the mobile phases. The method, validated through the calculation of all analytical parameters in accordance of International Guidelines, was applied to real saliva sample analysis collected from informed volunteers. The proposed approach that included the use of sol-gel polytetrahydrofuran (sol-gel PTHF) sorbent immobilized on cellulose support and C18 stationary phase used in HPLC, showed high potential as a fast tool for future clinical and forensic applications. The herein reported results encourage potential future application of FPSE in the forensic field. Furthermore, the FPSE membrane was tested in dried saliva spot mode (DSS) in order to check its potential use as a sampling device, also for forensic applications.

Effects and Mechanism of Action of PX-478 in Oxygen-Induced Retinopathy in Mice.

IMPORTANCE: Retinopathy of prematurity (ROP) is an important risk factor for blindness in children due to neovascularization (NV). Hypoxia stimulates the formation of NV, as retinal hypoxia affects the stability and function of hypoxia-inducible factor (HIF) transcription factors. The purpose of this study is to study the mechanism of ROP and provide theoretical basis for clinical treatment of ROP. OBJECTIVE: In the present study, we used a mouse model of oxygen-induced retinopathy (OIR) to demonstrate the effects of the HIF-1α inhibitor PX-478 on OIR, and to determine its mechanism of action, to provide a theoretical basis for the clinical treatment of ROP. MATERIALS AND METHODS: The OIR mouse model was induced by exposing neonatal mouse pups and their mothers to 75 ± 5% oxygen from postnatal day 7 (P7) to P12, before being returned to room air from P12 to P17. Flat mount analyses were performed at P12 and P17. Hif1a, Hif2a, Hif3a, and Vegfa mRNA were detected by reverse transcription-polymerase chain reaction in OIR mice at P12 and P17. Hif1a and Vegfa mRNA were detected in OIR mice at P12 and P17 treatment with PX-478. Western blot analyses were used to assess the levels of HIF-1α, VEGF-A, and EPO before and after treatment with PX-478 at P12 and P17. RESULTS: Hif1a mRNA was increased in OIR mice at P12 and P17, while Vegfa mRNA was increased at P12 and P17. HIF-1α, VEGF-A, and EPO protein levels were increased in OIR mice at P12 and P17, as compared to control mice at the same age (all p < 0.05). Inhibition of HIF-1α by injection of PX-478 in OIR mice (P9-P16) caused a decrease in the retinal avascular area at P12 and P17 (both p < 0.05), NV areas at P17 (p < 0.05), Vegfa mRNA decreased at P12 and P17, as compared to control mice (p < 0.05), and VEGF-A and EPO protein levels at P12 and P17, as compared to control mice. Our study found that there were PX-478 both retina and vitreous body of OIR. Inhibition of HIF-1α by injection of PX-478 in OIR mice caused a decrease in the retinal avascular area at P12 and P17, NV areas decreased at P17, VEGF-A and EPO protein levels at P12 and P17. Endothelial cell migration assays and cell tube formation indication PX-478 attenuate cell migration and significantly weakened the cell cavity formation under the condition of hypoxia. CONCLUSION: HIF-1α plays a main role in OIR and can be considered a therapeutic target in OIR by suppressing downstream angiogenic factors, PX-478 decreasing the retinal avascular area and NV.

Quantitative determination of characteristic components from compound of Lysionotus pauciflorus Maxim. by LC-MS/MS and its application to a pharmacokinetic study.

Tuberculosis of cervical lymph nodes is called scrofula in Traditional Chinese Medicine (TCM). Clinical manifestation is that unilateral or bilateral neck can have multiple enlarged lymph nodes of different sizes. Current therapeutic drugs include Lysionotus pauciflorus Maxim. tablets and compound of Lysionotus pauciflorus Maxim., which have a significant effect on tuberculosis of cervical lymph nodes. This compound is composed of three herbs, Lysionotus pauciflorus Maxim., Prunella vulgaris L. and Artemisia argyi Levl.et Vant. A selective and sensitive LC-MS/MS method was established and validated in rat plasma for the first time. Chromatographic separation was achieved on a Wonda Cract ODS-2 C18 Column (150 mm × 4.6 mm, 5 µm). The mobile phase contained 0.1% formic acid aqueous solution and acetonitrile with a flow rate of 0.8 mL/min. The detection was performed in negative electrospray ionization mode and the precursor/product ion transitions of six components and internal standard (IS) sulfamethoxazole were quantified in multiple reaction monitoring (MRM) using QTRAP-3200 MS/MS. The method fulfilled US Food and Drug Administration guidelines for selectivity, sensitivity, accuracy, precision, matrix effect, extraction recovery, dilution integrity, and stability. This proposed method was then successfully applied to a pharmacokinetic study after oral administration of 10 mL/kg compound extracts in rats. The pharmacokinetic parameters and plasma concentration-time profiles would prove valuable in pre-clinical and clinical investigations on the disposition of compound medicine.

Pharmacokinetics of ambrisentan in a patient with Pulmonary Arterial Hypertension and a total gastrectomy.

Significant advances have been made in the treatment of arterial pulmonary hypertension (PAH). However, no studies to date have assessed the impact of altered gastrointestinal (GI) anatomy or absorption on the efficacy and bioavailability of oral medications in the treatment of PAH. Here, we describe the treatment of a patient with PAH initially treated with epoprostenol. Subsequently, an intractable upper GI bleed required a total gastrectomy. With epoprostenol, there was near normalization of hemodynamics and she wished to attempt transition to an oral regimen. However, since it was not clear whether oral agents (specifically ambrisentan) would be absorbed and, if so, what the appropriate dose would be, we performed pharmacologic evaluation of ambrisentan absorption in this patient. These investigations identified an effective dose which led to successful transition from epoprostenol.

Identification of sulfonyl-loxoprofen as novel phase 2 conjugate in rat.

Loxoprofen is a prodrug that exerts strong analgesic and anti-inflammatory effects through its active trans-alcohol metabolite, which is produced in the liver by carbonyl reductase. Previous metabolic studies have evaluated loxoprofen, but its sulfate and taurine conjugates have not yet been studied. We characterized the metabolomic profile of loxoprofen in rat plasma, urine, and feces using high-resolution mass spectrometry. We identified 17 metabolites of loxoprofen in the three different biological matrices, 13 of which were detected in plasma and feces and 16 in urine. Amongst these metabolites, two novel taurine conjugates (M12 and M13) and two novel acyl glucuronides (M14, M15) were identified for the first time in rats. In addition, we detected three novel sulfate conjugates (M9, M10, and M11) of loxoprofen. Further study of these metabolites of loxoprofen is essential in order to assess their potency and toxicity.

Comparison of Blood Profiles of γ-Oryzanol and Ferulic Acid in Rats after Oral Intake of γ-Oryzanol.

γ-Oryzanol (OZ), a bioactive phytochemical abundant in cereals such as rice, has been reported to be mainly hydrolyzed to ferulic acid (FA) in the body. Meanwhile, in our previous study, we revealed that a part of OZ is absorbed into the body and exists in its intact form. However, the comprehensive absorption profile of OZ and its metabolites (e.g., FA) after OZ intake has not been fully elucidated yet. Therefore, in this study, we measured the concentrations of OZ, FA, and FA conjugates (i.e., FA sulfate and glucuronide) in the blood of rats with the use of HPLC-MS/MS after a single oral administration of 300 µmol/kg body weight of rice bran OZ (RBOZ). As a result, intact OZ along with FA and FA conjugates existed in the blood, which implied that these constituents may all contribute to the physiological effects under OZ intake. Additionally, when an equimolar amount of FA (300 µmol/kg body weight) was administered, it was found that the absorption profile of FA was significantly different from that when RBOZ was administered.

A Phase I Study to Show the Relative Bioavailability and Bioequivalence of Fixed-Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects.

PURPOSE: Pulmonary arterial hypertension (PAH) is a life-threatening disease that typically causes shortness of breath and exercise intolerance. Combination therapy with ambrisentan and tadalafil has proven to be more effective at preventing clinical failure events in patients with PAH than either drug alone. The aim of this study was to evaluate the bioequivalence of an ambrisentan/tadalafil fixed-dose combination (FDC) compared with co-administration of the 2 monotherapies. METHODS: This 3-part, randomized, single-dose, open-label crossover study was conducted in healthy volunteers. The first part of the study consisted of a 5-way crossover that compared the relative bioavailability of 4 FDC formulations (10-mg ambrisentan + 40-mg tadalafil) with co-administered reference monotherapies. One formulation was selected and its relative bioavailability was assessed when produced in 3 different granulation sizes during the second part of the study. In the third part of the study, the bioequivalence of the candidate FDC with the reference monotherapies was evaluated for the 10-mg/40-mg dose strength, in addition to 2 other dose strengths (5 mg/20 mg and 5 mg/40 mg). For all parts of the study, blood samples were taken at regular intervals after each dose, ambrisentan and tadalafil concentrations determined, and pharmacokinetic (PK) parameters (Cmax, AUC0-∞, and AUC0-t) obtained. Test/reference ratios of the geometric means of PK parameters were used to evaluate bioequivalence. Safety and tolerability were assessed by recording adverse events and monitoring vital signs, ECGs, and clinical laboratory data. FINDINGS: Of the 174 subjects screened for eligibility, 112 were allocated to a randomized treatment sequence across all study parts, and 100 completed their full assigned treatments. All 4 FDC formulations tested during part 1 of the study yielded PK parameters similar those of the reference treatments. In part 2, granulation size was found to not affect the relative bioavailability of the selected formulation. In part 3, the selected FDC was found to be bioequivalent to co-administration of the monotherapies in both the fasted and fed states. The FDC was also found to be bioequivalent to the reference treatments at the 2 additional dose strengths. All but one of the adverse events was mild to moderate in intensity, and no serious adverse events were reported. IMPLICATIONS: An ambrisentan/tadalafil FDC was bioequivalent to concurrently administered monotherapies and therefore represents a viable alternative treatment to co-administration. Use of an FDC is likely to be associated with reduced costs and improved patient compliance. ClinicalTrials.gov identifier: NCT02688387.

Chitosan based thermosensitive injectable hydrogels for controlled delivery of loxoprofen: development, characterization and in-vivo evaluation.

Oral drug delivery is natural, most acceptable and desirable route for nearly all drugs, but many drugs like NSAIDs when delivered by this route cause gastrointestinal irritation, gastric bleeding, ulcers, and many undesirable effects which limits their usage by oral delivery. Moreover, it is almost impossible to control the release of a drug in a targeted location in body. We developed thermo-responsive chitosan-co-poly(N-isopropyl-acrylamide) injectable hydrogel as an alternative for the gastro-protective and controlled delivery of loxoprofen sodium as a model drug. A free radical polymerization technique was used to synthesize thermo-responsive hydrogel by cross-linking chitosan HCl with NIPAAM using glutaraldehyde as cross-linker. Confirmation of crosslinked hydrogel structure was done by Fourier transform infrared spectra (FTIR). The thermal stability of hydrogel was confirmed through thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The scanning electron microscopy (SEM) was performed to evaluate the structural morphology of cross-linked hydrogel. To evaluate the rheological behavior of hydrogel with increasing temperature, rheological study was performed. Swelling and in vitro drug release studies were carried out under various temperature and pH conditions. The swelling study revealed that maximum swelling was observed at low pH (pH 1.2) and low temperature (25 °C) compared to the high range of pH and temperature and it resulted in quick release of the drug. The high range of pH (7.4) and temperature (37 °C) however caused controlled release of the drug. The in vivo evaluation of the developed hydrogel in rabbits demonstrated the controlled release behavior of fabricated system.

Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats.

Saroglitazar, a PPAR αÒ® agonist, is currently undergoing global development for the treatment of NASH and other indications. Saroglitazar showed CYP2C8 inhibition in human liver microsomes (IC50: 2.9 µM). The aim was to carry out drug-drug interaction (DDI) studies in Wistar rats using saroglitazar (perpetrator drug) with five CYP2C8 substrates. Also, the in vitro CYP2C8 inhibitory potential of saroglitazar in rat liver microsomes (RLM) was evaluated to justify use of preclinical model. The oral pharmacokinetics of various CYP2C8 substrates; montelukast, rosiglitazone, pioglitazone, repaglinide and intravenous pharmacokinetics of paclitaxel was assessed in the presence/absence of oral saroglitazar (4 mg/kg) in Wistar rats. A separate study was performed to assess the oral pharmacokinetics of saroglitazar. Serial blood samples were collected from all studies and the harvested plasma were stored frozen until bioanalysis. LC-MS/MS was used for the analysis of various analytes; concentration data was subjected to noncompartmental pharmacokinetic analysis. Statistical tests (unpaired t-test) were employed to judge the level of DDI. Generally, the pharmacokinetics of CYP2C8 substrates was not affected by the concomitant intake of saroglitazar as judged by the overall exposure (AUC0-last and AUC0-inf) and elimination half-life. The CYP2C8 IC50 of 4.5 µM in RLM for saroglitazar, supported the use of rats for this DDI study. In conclusion, pharmacokinetic data of diverse CYP2C8 substrates suggested that coadministration of saroglitazar did not cause clinically relevant DDI.

Natural product derived privileged scaffolds in drug discovery.

The biological activity and structural diversity of natural products are unsurpassed by any available synthetic screening libraries. As such, these privileged scaffolds serve as important, biologically prevalidated platforms for the design of compound libraries in the search for new drug candidates. Recent progress has focussed on improving the potency, selectivity and pharmacokinetics of bioactive natural products through structural modification, leading to the emergence of a number of drug-like lead compounds. Here, we review recent advances in the exploitation of terpenoid, polyketide, phenylpropanoid and alkaloid natural product scaffolds for inspiration in the design and development of important new drug candidates.

Evaluation of γ-oryzanol Accumulation and Lipid Metabolism in the Body of Mice Following Long-Term Administration of γ-oryzanol.

γ-Oryzanol (OZ), abundant in rice bran oil, has gained attention due to its physiological activities (e.g., lipid-lowering effects). However, the absorption and metabolism of orally ingested OZ have not yet been fully elucidated. In this study, diets containing normal or high contents of OZ were fed to obesity model mice for 8 weeks, and OZ concentrations in plasma and organs were analyzed by HPLC-MS/MS. To evaluate the relationship between OZ accumulation and lipid metabolism in vivo, lipid concentrations in the mice plasma and liver were also measured. As a result, the accumulation of intact OZ in plasma and organs was seen in mice fed diets containing OZ, where mice fed diets containing higher OZ contents demonstrated higher levels of OZ accumulation and lower amounts of plasma lipids. These results, in combination with our additional data from a single oral administration test, suggest the possibility that intact OZ, along with its metabolites (e.g., ferulic acid), is biologically-active.

Pharmacokinetics of vitamin E, γ-oryzanol, and ferulic acid in healthy humans after the ingestion of a rice bran-enriched porridge prepared with water or with milk.

PURPOSE: In this study, we investigated the absorption and excretion kinetics of antioxidant dietary phytochemicals (vitamin E, γ-oryzanol, and ferulic acid) in healthy humans after the ingestion of an oatmeal porridge supplemented with rice bran extract (RBE) prepared with water or with whole milk, and we compared it with the intake of an equivalent dose of the rice bran content, in the form of RBE oil. METHODS: Twelve healthy volunteers (6 men and 6 women) orally ingested RBE oil (2 g) or RBE-enriched porridge (35 g, including 2-g RBE) with water or with milk, in a three-armed, crossover trial. Blood and urine samples were collected at baseline and up to 24 h after intake. Vitamin E (α-, ß-, γ-, and δ-tocopherols and tocotrienols), ferulic acid (FA), and γ-oryzanol (ORY) were quantified by HPLC. RESULTS: The ingestion of RBE-fortified oatmeal porridge and RBE oil significantly increased FA concentrations in plasma, showing faster absorption and higher maximum plasma concentrations after the intake of the porridges, irrespective of the addition of water or milk. At least part of the FA could have been hydrolyzed from ORY. However, plasma vitamin E concentrations did not increase from baseline, and no intact FA esters (cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, campesteryl ferulate, and ß-sitosteryl ferulate) were detected in plasma or urine with any of the meal treatments. CONCLUSIONS: Rice bran extract-enriched porridge and, to a lesser extent, RBE oil, provide relevant sources of bioaccessible and bioavailable ferulic acid, and could be further developed into functional foods with health potential.

Proteomic Analysis and NIR-II Imaging of MCM2 Protein in Hepatocellular Carcinoma.

Targeted therapy of hepatocellular carcinoma (HCC) is essential for improved therapies. Therefore, identification of key targets specifically to HCC is an urgent requirement. Herein, an iTRAQ quantitative proteomic approach was employed to identify differentially expressed proteins in HCC tumor tissues. Of the upregulated tumor-related proteins, minichromosome maintenance 2 (MCM2), a DNA replication licensing factor, was one of the most significantly altered proteins, and its overexpression was confirmed using tissue microarray. Clinicopathological analysis of multiple cohorts of HCC patients indicated that overexpression of MCM2 was validated in 89.8% tumor tissues and strongly correlated with clinical stage. Furthermore, siRNA-mediated repression of MCM2 expression resulted in significant suppression of the HepG2 cell cycle and proliferation through the cyclin D-dependent kinases (CDKs) 2/7 pathway. Finally, the first small molecule-based MCM2-targeted NIR-II probe CH1055-MCM2 was concisely generated and subsequently evaluated in mice bearing HepG2 xenografts. The excellent imaging properties such as good tumor uptake and high tumor contrast and specificity were achieved in the small animal models. This analytical strategy can determine novel accessible targets of HCC useful for imaging and therapy.