Pharmacokinetic Study In Rats Research Articles

LC-MS/MS method assay for simultaneous determination of the pretomanid and pyrazinamide in rat plasma by LC-MS/MS: Assessment of pharmacokinetic drug-drug interaction study

AbstractIn the present study, an LC-MS/MS method allowing to quantify pretomanid and pyrazinamide simultaneously in rat plasma was developed. Chromatographic separation was achieved on an Agilent Eclipse plus C18 column (100 mm × 2.1 mm, 3.5 μm; Agilent, USA) and maintained at 30 °C. Multiple reaction monitoring (MRM) using positive-ion ESI mode to monitor ion transitions of m/z 360.1 → m/z 175.1 for pretomanid, m/z 124.1 → m/z 81.0 for pyrazinamide, m/z 172.1 → m/z 128.1 for metronidazole (IS). The calibration curves showed good linear relationships over the concentration range of 50–7,500 ng mL−1 for pretomanid and 500–75,000 ng mL−1 for pyrazinamide. The precision and accuracy were below 15% and within ±15% of the nominal concentrations, respectively. The selectivity, recovery and matrix effect of this method were all within acceptable limits of bioanalytics. The method was applied to the analysis of plasma samples from pharmacokinetic studies in rats. The results show that the main pharmacokinetic parameters of pyrazinamide, namely, Tmax, t1/2, and AUC(0–t), decreased in the combined group than in the alone group.

AmyP53, a Therapeutic Peptide Candidate for the Treatment of Alzheimer's and Parkinson's Disease: Safety, Stability, Pharmacokinetics Parameters and Nose-to Brain Delivery.

Neurodegenerative disorders are a major public health issue. Despite decades of research efforts, we are still seeking an efficient cure for these pathologies. The initial paradigm of large aggregates of amyloid proteins (amyloid plaques, Lewis bodies) as the root cause of Alzheimer's and Parkinson's diseases has been mostly dismissed. Instead, membrane-bound oligomers forming Ca2+-permeable amyloid pores are now considered appropriate targets for these diseases. Over the last 20 years, our group deciphered the molecular mechanisms of amyloid pore formation, which appeared to involve a common pathway for all amyloid proteins, including Aβ (Alzheimer) and α-synuclein (Parkinson). We then designed a short peptide (AmyP53), which prevents amyloid pore formation by targeting gangliosides, the plasma membrane receptors of amyloid proteins. Herein, we show that aqueous solutions of AmyP53 are remarkably stable upon storage at temperatures up to 45 °C for several months. AmyP53 appeared to be more stable in whole blood than in plasma. Pharmacokinetics studies in rats demonstrated that the peptide can rapidly and safely reach the brain after intranasal administration. The data suggest both the direct transport of AmyP53 via the olfactory bulb (and/or the trigeminal nerve) and an indirect transport via the circulation and the blood-brain barrier. In vitro experiments confirmed that AmyP53 is as active as cargo peptides in crossing the blood-brain barrier, consistent with its amino acid sequence specificities and physicochemical properties. Overall, these data open a route for the use of a nasal spray formulation of AmyP53 for the prevention and/or treatment of Alzheimer's and Parkinson's diseases in future clinical trials in humans.

Ultra-high performance supercritical fluid chromatography-tandem mass spectrometry method for simultaneous determination of atorvastatin, 2-hydroxy atorvastatin, and tangeretin in rat plasma and its application to the pharmacokinetic study.

Recent studies strongly suggest that atorvastatin combination therapy with tangeretin could be beneficial in the treatment of hyperlipidemia. This study aimed to investigate the pharmacokinetic interactions among atorvastatin, its active metabolite 2-hydroxy atorvastatin, and tangeretin after oral administration of atorvastatin with tangeretin in rats. A rapid, selective, and sensitive assay was developed and validated based on ultra-high performance supercritical fluid chromatography-tandem mass spectrometry for the simultaneous measurement of atorvastatin, 2-hydroxy atorvastatin, and tangeretin concentrations in rat plasma. Chromatographic separation of the analytes was conducted on an ACQUITY Torus 1-AA column in gradient elution mode. The mass transition ion pairs were m/z 559.0→440.0 for atorvastatin, m/z 575.2→440.0 for 2-hydroxy atorvastatin, m/z 373.0→358.1 for tangeretin, and m/z 254.8→136.7 for daidzein (internal standard). Calibration curves showed good linear correlations at the following concentration range: 1-400 (r = 0.9952), 1-400 (r = 0.9980), and 3-1200 (r = 0.9945) for atorvastatin, 2-hydroxy atorvastatin, and tangeretin, respectively. The method was fully validated and satisfied the acceptance criteria recommended by the United States Food and Drug Administration. Finally, it was successfully applied in a pharmacokinetic study in rats to evaluate the pharmacokinetic behavior of atorvastatin, 2-hydroxy atorvastatin, and tangeretin.

LC-MS/MS determination of GTS-201, a dipeptide mimetic of the brain-derived neurotrophic factor, and neurotransmitter metabolites with application to a pharmacokinetic study in rats

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family with diverse psychopharmacological effects including antidepressant and anxiolytic actions. However, the clinical use of BDNF is limited due to its poor pharmacokinetic properties. The development of low-molecular-weight BDNF mimetics passing through the blood-brain barrier is an emerging strategy for improved managing psychiatric diseases. The present study characterizes a novel dipeptide mimetic of the 2nd BDNF loop named GTS-201, which exhibits psychotropic properties in experimental animal models of anxiety and alcohol dependence. The aim of this work was to study the pharmacokinetics of GTS-201 in rats at a saturating dosage of 5 mg/kg applied by the intraperitoneal route and to characterize the effects on neurotransmitter levels in the blood and brain. The maximum concentration (Cmax) of GTS-201 in the plasma (867 ± 69 ng/ml) was recorded at 35 ± 7.7 min after administration (Tmax) with a half-elimination period (T1/2) of 19.5 ± 1.8 min, while in the brain tissue Cmax was 14.92 ± 3.11 ng/ml, Tmax was 40.0 ± 7.7 min and T1/2 were 87.5 ± 12.7 min. The relative tissue availability of the GTS-201 for the brain reached 2.9%. At the dose applied, GTS-201 induced a significant increase of serotonin (5-fold) and dopamine levels in the brain tissue (8-fold) along with a decrease in cortisol content in blood plasma 45 min after acute administration. In summary, GTS-201 crosses the blood-brain barrier after acute administration and affects the activity of serotonergic and dopaminergic systems, which may underlie its neuropsychotropic effects described previously.

Effect of phosphatidylcholine in bentonite-quetiapine complex on enhancing drug release and oral bioavailability

Bentonite (BT) is a biocompatible clay mineral that has advantageous properties as a pharmaceutical excipient. However, the application of BT in controlled-release oral formulations has been challenging due to incomplete drug release from BT-drug complexes. The objective of this study was to investigate the effect of modifying BT with zwitterionic phosphatidylcholine (PC) to enhance the dissolution of drugs, thereby increasing their oral bioavailability. Quetiapine (QTP) was chosen as a model drug, and the composition of the complex (BT-PC-QTP) was optimized to have the maximum QTP content and increase the total amount of QTP released. The in vitro release study showed that the incorporation of an appropriate amount of PC into BT improved the low release rate of the BT-QTP complex at pH 7.4, while the pH-dependent release property of BT was maintained. In an in vivo pharmacokinetic study in rats, the oral administration of the BT-PC-QTP complex showed significantly higher Cmax and AUC values than the BT-QTP complex. Moreover, BT-PC-QTP showed a 2.4-fold enhancement of oral bioavailability compared to the QTP powder group. The scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), and differential scanning calorimetry (DSC) studies confirmed that the intercalation of PC and QTP into BT resulted in the adsorption of QTP in an amorphous state. The characterization of the nanoparticles generated from the BT-PC-QTP complex supported that PC enhanced the dissolution of QTP by forming nanosized PC particles. Taken together, the modification of BT with PC can be applied in pharmaceutical industry as a platform strategy to control the release of the BT-drug complex and enhance the oral bioavailability of poorly water-soluble drugs.

Atazanavir-Concentrate Loaded Soft Gelatin Capsule for Enhanced Concentration in Plasma, Brain, Spleen, and Lymphatics.

This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain, spleen, and lymphatics beneficial in the significant reduction of viral load in HIV infection. For this purpose, ATV-concentrate in the presence and absence of Soluplus with corn oil, oleic acid, tween 80, and propylene glycol was developed. The developed ATV-concentrate was found to have enhanced dispersibility with no signs of precipitation after dilution with simulated G.I fluid as evident from particle size (16.49±0.32 nm) and PDI (0.217±0.02) analysis. The rheological and molecular docking studies explainedthe reduction of viscosity of SuATV-C due to the intermolecular H-bond between ATV and Soluplus that helps to retard crystallization. The shell of the soft gelatin capsule retains its integrity when subjected to a folding endurance test on a texture analyzer depicting that the concentrate did not affect the integrity of the soft gelatin capsule shell. An ex vivo and in vivo pharmacokinetic study in rats revealed that the SuATV-C soft gelatin capsule (SuATV-C SGC) indicated 2.9 fold improvement in rate and extent of permeation and absorption than that of ATV-suspension. The tissue distribution study also exhibited higher drug concentration in the brain (2.5 fold), lymph nodes (2.7 fold), and spleen (1.2 fold) administered with SuATV-C SGC, revealing the overwhelming influence of Soluplus and corn oil. In a nutshell, these studies demonstrated that SuATV-C SGC seems to have the potential to deliver an anti-retroviral drug to the viral sanctuaries for the better management of HIV.

Translational pharmacokinetics of a novel bispecific antibody against Ebola virus (MBS77E) from animal to human by PBPK modeling & simulation

The goal of this study was to construct a PBPK model to accelerate the translation of MBS77E, a humanized bispecific antibody against the Ebola virus. In-depth nonclinical pharmacokinetic studies in rats, monkeys, wild-type mice and transgenic mice were conducted. The pH-dependent affinities (KD) of MBS77E to recombinant FcRn of different species were determined by surface plasmon resonance analysis. A mechanistic whole-body PBPK model of MBS77E was developed and validated in the assessment of PK profiles and tissue distributions in preclinical models. This PBPK model was finally used to predict human PK behaviors of MBS77E. Simulations from the PBPK model with measured and fitted parameters were able to yield good predictions of the serum and tissue pharmacokinetic parameters of MBS77E within 2-fold errors. The predicted serum concentration in humans was able to maintain a sufficiently high level for more than 14 days after 50 mg/kg i.v. administrating. This achievement unlocks that PBPK modeling is a powerful tool to gain insights into the properties of antibody drugs. It guided experimental efforts to obtain necessary information before entry into humans.

A high throughput method for Monitoring of Sorafenib, regorafenib, cabozantinib and their metabolites with UPLC-MS/MS in rat plasma

As multi-targeted tyrosine kinase inhibitors, sorafenib, regorafenib and cabozantinib are widely used in hepatocellular carcinoma (HCC) for systemic therapies with anti-proliferative and anti-angiogenic effects. Nevertheless, adverse effects or insufficient efficacy appear frequently due to the plasma concentration with individual variability of these drugs. To ensure the curative effect and safety by therapeutic drug monitoring (TDM), this study developed a high throughput method to quantify sorafenib, regorafenib, cabozantinib and their active metabolites in plasma simultaneously. The chromatographic separation analysis achievement was performed on a Waters-ACQUITY UPLC BEH C18 column by UPLC-MS/MS system using a gradient elution of solvent A (acetonitrile) and solvent B (water with 0.1% formic acid) in 3.0 min. This method presented satisfactory results of specificity, precision (the intra-day coefficient of variation was between 2.5% and 6.6%, and the inter-day coefficient of variation was between 4.0% and 11.1%) and accuracy (within ±15% for intra-day and inter-day), as well as the stability under certain conditions, the matrix effect in plasma, and extraction recovery (75.6%–94.4%). The linearity of each analyte in the proper concentration scope indicated excellent. This study strictly complied with the performance rules of assay validation in biological medium proposed by FDA and was successfully applied to the pharmacokinetic study in rats. Thus, it would be an advantageous option to research the relationship between concentration-efficacy and concentration-toxic in HCC patients who were supposed to take these medications.

Towards more efficient inhalable chemotherapy: Fabrication of nanodiamonds-releasing microspheres

Nanodiamonds (NDs) are among the most promising chemotherapy vectors, however, they tend to aggregate upon storage, or when exposed to mild changes in pH or ionic strength. Therefore, fabrication of dried NDs with minimal change in particle size is highly desirable. In this study, we have developed a dried powder form of NDs with controlled particle size to be eligible for pulmonary delivery, after screening different drying protectants for their effect on NDs particle size and surface charge. Results showed that the nanospray-drying process in the presence of mannitol prevented the aggregation of NDs. Nanospray-dried NDs microparticles exhibited an optimal aerodynamic size for pulmonary delivery, and the in vitro aerosol deposition testing showed that NDs-embedded mannitol microspheres could deliver more than half of the emitted fraction to the lower stage of the Twin impinger device; indicating high pulmonary delivery potential. Upon loading NDs with doxorubicin (NDX) prior to spray dryng, they were able to deliver 2.6 times more drug to A549 lung cancer cell line compared to the free drug. Pharmacokinetics study in rats showed that inhaled NDX microparticles could efficiently limit the biodistribution of the drug to the lungs, and minimize the drug fraction reaching the systemic circulation. To conclude, nanospray-dried NDs microparticles present a promising vehicle for the pulmonary delivery of chemotherapeutic agents for treatment of lung cancer.

Development of a UPLC-MS/MS method for the determination of orelabrutinib in rat plasma and its application in pharmacokinetics.

The aim of the present study was to establish an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of orelabrutinib in rat plasma using futibatinib as internal standard (IS), and to apply it for a pharmacokinetic study in rats. Orelabrutinib was extracted from plasma by protein precipitation and quantitatively analyzed by UPLC-MS/MS. An Acquity UPLC BEH C18 column was used for rapid separation by gradient elution using 0.1% formic acid and acetonitrile as mobile phases. The validation results of bioanalytical methodology showed that the linearity of orelabrutinib in plasma samples was good within the concentration range of 1–2000 ng/ml. The lower limit of quantification (LLOQ) was 1 ng/ml. The precision of orelabrutinib ranged from 1.4% to 11.5%, with intra-day and inter-day accuracy ranging from −5.7% to 7.7% and −0.2% to 12.5%, respectively. The selectivity, stability, matrix effect and recovery of the method all met the requirements of quantitative analysis of biological samples. The method was simple, sensitive, accurate and specific, and had high recovery rate. It also could be successfully applied to the pharmacokinetic study of rats.

Combining lipid based drug delivery and amorphous solid dispersions for improved oral drug absorption of a poorly water-soluble drug.

Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the aim of enhancing physical stability, solubilization and absorption of the model drug ritonavir. Ritonavir was loaded at a concentration above its saturation solubility (Seq) in the SNEDDS (superSNEDDS, 250% of Seq). An ASD of ritonavir with polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon® VA64) was prepared by ball milling. Relevant control formulations, which include conventional SNEDDS (90% of Seq), superSNEDDS with a physical mix of Kollidon® VA64 and ritonavir (superSNEDDS+PM) and an aqueous suspension of ritonavir were used. A pharmacokinetic (PK) study in rats was performed to assess the relative bioavailability of ritonavir after oral administration. This was followed by evaluating the formulations in a novel two-step in vitro lipolysis model simulating rat gastric and intestinal conditions. The addition of a ritonavir containing ASD to superSNEDDS increased the degree of supersaturation from 250% to 275% Seq in the superSNEDDS and the physical stability (absence of drug recrystallization) of the system from 48h to 1month under ambient conditions. The PK study in rats displayed significantly higher Cmax and AUC0-7h (3-fold increase) and faster Tmax for superSNEDDS+ASD compared to the conventional SNEDDS whilst containing 3 times less lipid than the latter. Furthermore, superSNEDDS+ASD were able to keep the drug solubilised during in vitro lipolysis to the same degree as the conventional SNEDDS. These findings suggest that dissolving an ASD in a superSNEDDS can contribute to the development of novel oral delivery systems with increased bioavailability for poorly water-soluble drugs.

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.