Pharmacokinetic Study In Rats Research Articles

Comparable Intestinal and Hepatic First-Pass Effect of YL-IPA08 on the Bioavailability and Effective Brain Exposure, a Rapid Anti-PTSD and Anti-Depression Compound.

YL-IPA08, exerting rapid antidepressant-like and anxiolytic-like effects on behaviors by translocator protein (TSPO) mediation, is a novel compound that has been discovered and developed at our institute. Fit-for-purpose pharmacokinetic properties is urgently needed to be discovered as early as possible for a new compound. YL-IPA08 exhibited low bioavailability (∼6%) during the preliminary pharmacokinetics study in rats after oral administration. Our aim was to determine how metabolic disposition by microsomal P450 enzymes in liver and intestine limited YL-IPA08’s bioavailability and further affected brain penetration to the target. Studies of in vitro metabolic stability and permeability combined with in vivo oral bioavailability, panel CYP inhibitor co-administration via different routes, and double cannulation rats were conducted to elucidate the intestinal and hepatic first-pass effect of YL-IPA08 on bioavailability. Unbound brain-to-plasma ratio (K p,uu) in rats was determined at steady state. Results indicated that P450-mediated elimination appeared to be important for its extensive first-pass effect with comparative contribution of gut (35%) and liver (17%), and no significant species difference was observed. The unbound concentration of YL-IPA08 in rat brain (6.5 pg/ml) was estimated based on K p,uu (0.18) and was slightly higher than in vitro TSPO-binding activity (4.9 pg/ml). Based on the onset efficacy of YL-IPA08 toward TPSO in brain and K p,uu, therapeutic human plasma concentration was predicted to be ∼27.2 ng/ml would easily be reached even with unfavorable bioavailability.

Pharmacokinetics and tissue distribution study of obtusifolin in rats by liquid chromatography-tandem mass spectrometry.

This paper reports the validation of an assay for obtusifolin based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its application to a preclinical pharmacokinetic study in rats. After sample preparation of plasma and tissue homogenates by protein precipitation, the analyte and internal standard (IS) were separated by a reversed-phase chromatographic system in a run time of 5.0 min and detected by negative ion electrospray ionization followed by selected reaction monitoring of the precursor-to-product ion transitions at m/z 283.0-268.1 for obtusifolin and m/z 329.0-314.1 for IS. The assay was linear in the concentration range 1.0-500 ng/ml with the LLOQ of 1.0 ng/ml. In the pharmacokinetic study of an intragastric administration of 1.3 mg/kg obtusifolin, the maximum plasma concentration of obtusifolin was 152.5 ± 62.3 ng/ml, reached at 0.39 ± 0.17 h. The AUC0-t and AUC0-∞ were 491.8 ± 256.7 and 501.7 ± 256.7 ng × h/ml, respectively, with an elimination half-life of 3.1 ± 0.7 h. Obtusifolin was rapidly distributed into tissues, with the highest distribution in the liver and less in the brain. These results will give some insights for further pharmacological investigation of obtusifolin.

Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo.

The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)2D3 in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)2D3 on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)2D3. Consistently, the in vitro metabolic kinetics (Vmax and CLint) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)2D3 treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CLNR) of BUP were significantly reduced by 1,25(OH)2D3, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CLR) of HBUP. Additionally, the AUC, CL, and CLNR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)2D3 in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (Vss) and lower plasma protein binding in 1,25(OH)2D3-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)2D3.

Development and validation of ultra-high-performance liquid chromatography-mass spectrometry method for the determination of raloxifene and its phase II metabolites in plasma: Application to pharmacokinetic studies in rats.

The aim of this study is to establish a reliable liquid chromatography-mass spectrometry method to simultaneously quantitate raloxifene, and its major metabolites, raloxifene-6-glucuronide, raloxifene-4'-glucuronide, and raloxifene-6-sulfate in rat plasma samples for pharmacokinetic studies. The separation of the analytes was achieved on a Waters BEH C18 column. Water (0.1% formic acid) and acetonitrile were used as the mobile phases for elution. A one-step protein precipitation using a mixture solvent was applied for plasma sample preparation. The method was validated following the FDA guidance. The results showed that the linear range were 1.95-1000nM for raloxifene-6-glucuronide, and raloxifene-4'-glucuronide, 0.195-100nM for raloxifene-6-sulfate, and 0.195-200nM for raloxifene, respectively. The lower limit of quantification was 1.95, 1.95, 0.195, and 0.195nM for raloxifene-6-glucuronide, raloxifene-4'-glucuronide, raloxifene-6-sulfate, and raloxifene, respectively. Only 20µl of plasma sample was required since the method is sensitive. The intra- and interday variance is <15% and the accuracy is within 85-115%. The variance of matrix effect and recovery were<15%. The method was successfully applied in a pharmacokinetic study in rats with oral administration of raloxifene.

Bioanalytical Assay Development and Validation for the Pharmacokinetic Study of GMC1, a Novel FKBP52 Co-chaperone Inhibitor for Castration Resistant Prostate Cancer.

Background: GMC1 (2-(1H-benzimidazol-2-ylsulfanyl)-N-[(Z)-(4-methoxyphenyl) methylideneamino] acetamide) effectively inhibits androgen receptor function by binding directly to FKBP52. This is a novel mechanism for the treatment of castration resistant prostate cancer (CRPC). Methods: an LC-MS/MS method was developed and validated to quantify GMC1 in plasma and urine from pharmacokinetics studies in rats. An ultra-high-performance liquid chromatography (UHPLC) system equipped with a Waters XTerra MS C18 column was used for chromatographic separation by gradient elution with 0.1% (v/v) formic acid in water and methanol. A Sciex 4000 QTRAP® mass spectrometer was used for analysis by multiple reaction monitoring (MRM) in positive mode; the specific ions [M+H]+ m/z 340.995 → m/z 191.000 and [M+H]+ m/z 266.013 → m/z 234.000 were monitored for GMC1 and internal standard (albendazole), respectively. Results: GMC1 and albendazole had retention times of 1.68 and 1.66 min, respectively. The calibration curves for the determination of GMC1 in rat plasma and urine were linear from 1–1000 ng/mL. The LC-MS/MS method was validated with intra- and inter-day accuracy and precision within the 15% acceptance limit. The extraction recovery values of GMC1 from rat plasma and urine were greater than 95.0 ± 2.1% and 97.6 ± 4.6%, respectively, with no significant interfering matrix effect. GMC1 is stable under expected sample handling, storage, preparation and LC-MS/MS analysis conditions. Conclusions: Pharmacokinetic evaluation of GMC1 revealed that the molecule has a biexponential disposition in rats, is distributed rapidly and extensively, has a long elimination half-life, and appears to be eliminated primarily by first order kinetics.

Mucoadhesive nanocrystal-in-microspheres with high drug loading capacity for bioavailability enhancement of silybin

Nanocrystals, due to high drug loading efficiency, have drawn large attention as nanotechnology to enhance solubility and bioavailability of poorly soluble drugs. However, most nanocrystals still encountered low oral absorption percentage due to its insufficient retention time in the gastrointestinal tract (GI). In this work, silybin (SB) as model drug was fabricated to nanocrystals, and further loaded into a mucoadhesive microsphere to increase the GI retention. Such mucoadhesive microspheres were prepared with a wet media milling technique followed by coagulation and film coating. Nanocrystals and microspheres were thoroughly characterized by diverse complementary techniques. As results, such delivery system displayed an encapsulation efficiency of approximately 100 % and a drug loading capacity of up to 35.41 ± 0.31 %. In addition, mucoadhesiveness test ex vivo conducted with rat intestine showed that film-coated microspheres were retained for more than 1 h. Benefiting from nanocrystals technology, the drug cumulative release percentage of the microspheres was remarkable improved compared to unprocessed one in vitro. Finally, pharmacokinetics studies in rats showed a significant 3-fold increase of drug oral bioavailability compared to unprocessed SB. The current study demonstrates that the developed delivery vehicle can enhance the bioavailability of SB by increasing its dissolution percentage as well as through extending retention time in the GI tract, and achieve high drug loading capacity.

Development of a Ultra-Performance LC–MS/MS Method for Quantification of Gw788388 and its Applications in Pharmacokinetic Study in Rats

Aim: GW788388 is a selective and orally active TGF-β1 receptor inhibitor that shows potent activity in renal fibrosis. We aimed to establish and validate a simple and sensitive ultra-performanceLC-MS/MSmethod for the determination of GW788388 in plasma samples. Methodology & results: GW788388 in rat plasma was processed with protein precipitation method and then separated on a C18 column. The calibration curve presented a good linearity in the range of 1.0-1200ng/ml, with satisfactory accuracy (relative error, [-17.5% < relative error<11.7%) and precision (CV <8.9%) for all quality control samples. After oral administration, GW788388 was absorbed quickly and reached a peak concentration of 595.3±60.2ng/mlafter 20min. Conclusion: The validated method provides a quantification method of GW788388 in rat plasma in detail, and can be utilized to successfully describe the pharmacokinetic profile of GW788388.

Development and Validation of a LC-MS/MS Method for Quantification of Mobocertinib (TAK-788) in Plasma and its Application to Pharmacokinetic Study in Rats.

An analytical method for the determination of mobocertinib, an investigational tyrosine kinase inhibitor, was developed and optimized by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rat plasma. Plasma samples were pretreated by the protein precipitation method with a methanol solution of osimertinib as the internal standard (IS). Chromatographic separation was performed using an Inertsil ODS-3 column (50 mm × 4.6 mm, I.D. 5 μm) with the temperature maintained at 40°C. The mobile phase consisted of water (containing 0.1% formic acid) and methanol in a gradient mode at a flow rate of 0.5 mL/min. Mass spectrometric detection was carried out in the selected reaction monitoring (SRM) mode with positive electrospray ionization, and the mass transitions of mobocertinib and osimertinib were m/z 587.01 → 71.88 and m/z 499.80 → 71.94, respectively. The method was validated in terms of selectivity, linearity, accuracy and precision, extraction recovery and matrix effect, stability and carryover as per the guidelines for bioanalytical method validation (FDA, 2018). The method was applied to the pharmacokinetic study of mobocertinib in rats by oral gavage at the doses of 2, 6, and 18 mg/kg. A total of 216 plasma samples from 18 rats were analyzed. The results showed good linearity over the range of 1-1000 ng/mL (R2 = 0.9957). The intra-batch accuracy was within 94.65-102.59% and the precision was within 5.49-10.46%. The inter-batch accuracy was within 97.08-102.25% with a precision of 7.54-10.13%. The extraction recovery and matrix factor were acceptable for the bioanalysis of mobocertinib. Additionally, mobocertinib was found to be stable under the detected conditions. Mobocertinib showed linear pharmacokinetic characteristics following oral administration to rats at 2.0-18.0 mg/kg. The developed and validated method was successfully employed in the pharmacokinetic study in rats following oral administration of mobocertinib at the doses of 2, 6, and 18 mg/kg.

A novel method for preparing stabilized amorphous solid dispersion drug formulations using acoustic fusion.

A diverse set of drug and polymer combinations have been effectively evaluated utilizing a newly developed method called acoustic fusion to form amorphous solid dispersions (ASD) on the mg-scale, indicating that this approach is a general procedure that can be applied for ASD drug formulations. We have demonstrated the effectiveness of this acoustic fusion process by generating amorphous solid dispersions of various BCS class 2 and 4 drug candidates, including torcetrapib, itraconazole, and lopinavir, with a variety of polymer systems, including HPMCAS (L, M, and H), copovidone, Soluplus®, PEG1500, Vitamin-E TPGS, Kolliphor EL, and Eudragit, etc. Formulations of these ASD drug products demonstrated significantly elevated solubility of the drug substance compared to the solubility of the crystalline form of the drug. Acoustic fusion products using the model drug torcetrapib in either HPMCAS-LF, copovidone + Vitamin-E TPGS, or Soluplus®, exhibited enhanced supersaturation solubility in aqueous buffer in vitro compared to the drug in crystalline form, indicating that the acoustic fusion process resulted in an amorphous solid dispersion state similar to those formed in spray drying (SD) or hot melt extrusion (HME) processes. In vivo dosing of formulations of the acoustic fusion products in a rat pharmacokinetic study at a dose level of 10 mg/kg resulted in an improvement in exposures of approximately 8-fold by AUC(0-24) in comparison to a conventional suspension formulation of the drug material in crystalline form, thus validating the efficiency of this novel acoustic fusion approach for elevating the bioperformance in preclinical studies.

Bioavailability Improvement of Carbamazepine via Oral Administration of Modified-Release Amorphous Solid Dispersions in Rats.

The purpose of this study was to improve the bioavailability of carbamazepine (CBZ), a poorly water-soluble antiepileptic drug, via modified-release amorphous solid dispersions (mr-ASD) by a thin film freezing (TFF) process. Three types of CBZ-mr-ASD with immediate-, delayed-, and controlled-release properties were successfully prepared with HPMC E3 (hydrophilic), L100-55 (enteric), and cellulose acetate (CA, lipophilic), defined as CBZ-ir-ASD, CBZ-dr-ASD, and CBZ-cr-ASD, respectively. A dry granulation method was used to prepare CBZ-mr-ASD capsule formulations. Various characterization techniques were applied to evaluate the physicochemical properties of CBZ-mr-ASD and the related capsules. The drug remained in an amorphous state when encapsulated within CBZ-mr-ASD, and the capsule formulation progress did not affect the performance of the dispersions. In dissolution tests, the preparations and the corresponding dosage forms similarly showed typical immediate-, delayed-, and controlled-release properties depending on the solubility of the polymers. Moreover, single-dose 24 h pharmacokinetic studies in rats indicated that CBZ-mr-ASD significantly enhanced the oral absorption of CBZ compared to that of crude CBZ. Increased oral absorption of CBZ was observed, especially in the CBZ-dr-ASD formulation, which showed a better pharmacokinetic profile than that of crude CBZ with 2.63- and 3.17-fold improved bioavailability of the drug and its main active metabolite carbamazepine 10,11-epoxide (CBZ-E).

Supersaturable self-microemulsifying drug delivery system enhances dissolution and bioavailability of telmisartan

To enhance the dissolution and oral bioavailability of telmisartan (TMS), a poorly water-soluble anti-hypertensive drug, a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) was developed. Amorphous alkalinized TMS (AAT) was formulated into a SMEDDS, composed of Capmul® MCM (oil), Cremophor® RH40 (surfactant), and tetraglycol (co-surfactant). Although the SMEDDS was rapidly dissolved (>80% within 5 min) in a limited condition (500 mL, pH 6.8), drug precipitation was observed over time, resulting in a decrease in dissolution levels. The precipitation was due to drug recrystallization, as determined by differential scanning calorimetry and powder X-ray diffraction analyses. Several polymers, including Soluplus® (SOL), were screened as precipitation inhibitors; ultimately, SuSMEDDS-SOL was prepared by admixing SOL and the SMEDDS at a 5:100 (w/w) ratio. SuSMEDDS-SOL was superior in terms of dissolution efficiency (>90% over 2 h) and dissolution-retaining time (no precipitation over 2 h). An in vivo pharmacokinetic study in rats revealed that the oral bioavailability of SuSMEDDS-SOL was 4.8-, 1.3-, and 1.2-fold greater than those of the TMS suspension, AAT solution, and SMEDDS, respectively. Therefore, SuSMEDDS-SOL is a promising candidate to enhance the dissolution and oral bioavailability of TMS.

Cationic self-nanoemulsifying formulations of tamoxifen with improved biopharmaceutical attributes and anticancer activity: Systematic development and evaluation

A cationic nanoemulsion of tamoxifen (Tmx) containing a charge inducer was developed for improving biopharmaceutical attributes and anticancer potential of the drug. The lipidic formulation constituted of corn oil, labrasol and transcutol HP and optimized using a mixture design by selecting these excipients as the independent variables. The formulation was evaluated for globule size, polydispersity index and drug release characteristics as the dependent variables. Oleylamine was incorporated into the optimized nanoemulsion for inducing a positive charge. The optimized cationic Tmx-nanoemulsion with 34%:48%:17% of the aforementioned excipients and 0.5% v/v of the charge inducer showed particle size of 138 nm and a polydispersity index 0.31, zeta potential +35.45 mV and more than 85% Tmx release in a 1 h time period. In vitro evaluation of the cytotoxicity, qualitative and quantitative uptake studies on Caco-2 and MCF-7 cells revealed satisfactory results. In vivo pharmacokinetic study in rats under fasting condition showed a significant increase in the rate and extent of drug absorption (2 to 4-folds) from the optimized cationic Tmx-nanoemulsion vis-à-vis the pure drug (p < 0.001). The results observed from the aforementioned studies construed significant augmentation in the biopharmaceutical performance and anticancer activity of the drug from the prepared cationic nanoemulsion.

Intragastric amorphous calcium carbonate consumption triggered generation of in situ hydrogel piece for sustained drug release.

Sustained-release systems in solid forms are widely accepted except for those patients with dysphagia such as the elderly and infants. Herein, we have developed a sustained-release oral drug solution by dispersing polyaspartic acid stabilized amorphous calcium carbonate (ACC) nanoparticles (NPs) (<100nm) in drug-containing sodium alginate (SA) solution (2%). It can be supposed that ACC NPs would consume in the gastrointestinal tract acid environment and provide calcium ions as the crosslinker for SA polymer solution to gain in situ hydrogels. The pre-gel solution system appeared a distinct reversible shear-thin characteristic with high viscosity and stability during storage. Whereas, it can regain fine flowability for convenient oral administration after slightly shaking. In this study, ACC NPs consumption triggered solution-gel transition of this drug-containing pre-gel solution system was demonstrated in simulated gastric solution and in vivo, with the distinct sustained drug release profiles lasting for 10h. In addition, pharmacokinetics studies in SD rats showed that the Tmax (up to 1.79±0.24h) and AUC0-12 (46.37±2.71μg/mL·h) of ACC/SA in situ hydrogels treated group were significantly higher (p<0.05) than that of free drug solution. Overall, these results highlighted a novel promising platform for oral administration of drugs, reduced dosing frequency, and high potential compliance for patients with dysphagia.

Simultaneous determination of sacubitrilat and fimasartan in rat plasma by a triple quad liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive mode.

An LC-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of fimasartan and sacubitrilat using positive ion mode. The protein precipitation method was employed for the extraction of fimasartan, sacubitrilat and alprazolam (internal standard) from rat heparinized plasma. Baseline separation of the analytes was accomplished using an ACE-5, C18 (4.6 × 50 mm) column and gradient elution of mobile phase A (5 mm ammonium formate and 0.1% formic acid in purified water) and B (acetonitrile:methanol, 80:20; v/v). All peaks of interest were eluted within a 5-min runtime. The quantitation was achieved in the selected reaction monitoring mode. The developed method was validated as per US Food and Drug Administration guidelines and met the pre-defined acceptance criteria. The method showed linearity from 5 to 10,000 ng/mL. The accuracy/precision of intra- and inter-batch assays was 96.64%/2.05% to 109.17%/13.70% and 100.74%/3.76% to 106.39%/9.75% for fimasartan and 100.02%/1.49% to 113.80%/9.38% and 100.75%/2.31% to 108.40%/7.74% for sacubitrilat, respectively, in rat plasma. Fimasartan and sacubitrilat remained stable in rat plasma at different experimental conditions up to 21 days. The developed method was sensitive, selective and applied successfully to monitor plasma concentrations of fimasartan and sacubitrilat in an oral rat pharmacokinetic study.

A validated LC-MS/MS method for the determination of RAF inhibitor LXH254: Application to pharmacokinetic study in rat.

In this study, a simple and sensitive UHPLC-ESI-MS/MS method was established for the determination of LXH254 in rat plasma. The developed method was validated according to the Food and Drug administration guidelines. After extraction using ethyl acetate, the sample was separated on an ACQUITY BEH C18 column. The mobile phase consisted of 2 mM ammonium acetate containing 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. The flow rate was 0.3 mL/min. A TSQ triple quadrupole mass spectrometer operated in positive-ion mode was used for mass detection, with multiple reaction monitoring transitions of m/z 503.3 > 459.1 and m/z 435.3 > 367.1 for LXH254 and olaparib (internal standard), respectively. An excellent linearity was achieved in the concentration range of 0.1-1000 ng/mL, with correlation coefficient >0.998. The mean recovery was more than 78.55%. Inter- and intra-day precision (percentage of relative standard deviation) did not exceed 12.87%, and accuracy was in the range of -2.50 to 13.50%. LXH254 was demonstrated to be stable under the tested storage conditions. The validated UHPLC-MS/MS method was further applied to the pharmacokinetic study of LXH254 in rat plasma after oral (2, 5, and 15 mg/kg) and intravenous (2 mg/kg) administrations. The pharmacokinetic study revealed that LXH254 showed low clearance, moderate bioavailability (~30%), and linear pharmacokinetic profile over the oral dose range of 2-15 mg/kg. To the best of our knowledge, this is the first report on the method development and validation of the determination of LXH254 and its application to pharmacokinetic study.

Application of a Scavenger Receptor A1-Targeted Polymeric Prodrug Platform for Lymphatic Drug Delivery in HIV.

We have developed a macromolecular prodrug platform based on poly(l-lysine succinylated) (PLS) that targets scavenger receptor A1 (SR-A1), a receptor expressed by myeloid and endothelial cells. We demonstrate the selective uptake of PLS by murine macrophage, RAW 264.7 cells, which was eliminated upon cotreatment with the SR-A inhibitor polyinosinic acid (poly I). Further, we observed no uptake of PLS in an SR-A1-deficient RAW 264.7 cell line, even after 24 h incubation. In mice, PLS distributed to lymphatic organs following i.v. injection, as observed by ex vivo fluorescent imaging, and accumulated in lymph nodes following both i.v. and i.d. administrations, based on immunohistochemical analysis with high-resolution microscopy. As a proof-of-concept, the HIV antiviral emtricitabine (FTC) was conjugated to the polymer's succinyl groups via ester bonds, with a drug loading of 14.2% (wt/wt). The prodrug (PLS-FTC) demonstrated controlled release properties in vitro with a release half-life of 15 h in human plasma and 29 h in esterase-inhibited plasma, indicating that drug release occurs through both enzymatic and nonenzymatic mechanisms. Upon incubation of PLS-FTC with human peripheral blood mononuclear cells (PBMCs), the released drug was converted to the active metabolite FTC triphosphate. In a pharmacokinetic study in rats, the prodrug achieved ∼7-19-fold higher concentrations in lymphatic tissues compared to those in FTC control, supporting lymphatic-targeted drug delivery. We believe that the SR-A1-targeted macromolecular PLS prodrug platform has extraordinary potential for the treatment of infectious diseases.

Do Phospholipids Boost or Attenuate Drug Absorption? In Vitro and In Vivo Evaluation of Mono- and Diacyl Phospholipid-Based Solid Dispersions of Celecoxib

Phospholipids are amphiphilic lipids with versatile properties making them promising excipients for enabling formulations for oral drug delivery. Unfortunately, systematic studies on how phospholipid type and content affect oral absorption are rare. Often, only one phospholipid type is used for the formulation development and only one formulation, optimized according to in vitro parameters, is included in oral bioavailability studies. Using this approach, it is unclear if a certain in vitro parameter is predictive for the in vivo performance. In this study, a labor-saving in vitro permeation screening method was combined with a pharmacokinetic study in rats to for the first time systematically compare two types of phospholipid-based solid dispersions. The dispersions contained the drug celecoxib and monoacyl or diacyl phosphatidylcholine at different drug-to-phospholipid ratios. The in vitro screening revealed: 1) none of the formulations with high phospholipid content increased permeation, 2) phospholipid content was negatively correlated with permeation, and 3) mono and diacyl-phosphatidylcholine formulations performed equally. The pharmacokinetic study revealed: 1) At low phospholipid content absorption was enhanced, 2) phospholipid content was negatively correlated with absorption, and 3) monoacyl and diacyl phosphatidylcholine formulations performed equally. Apart from the reference (suspension), the in vitro permeation screening thus predicted the formulations in vivo performance.

NIR-II-Activated Yolk-Shell Nanostructures as an Intelligent Platform for Parkinsonian Therapy.

Despite the relative severity of Parkinson's disease (PD), to date, there has been only limited success in preventing or treating this condition owing to the low permeability of the blood-brain barrier (BBB), which makes the cerebral delivery of pharmaceutical agents very challenging. In the present study, we explored an approach to increasing BBB permeability via the use of mesoporous silica-encapsulated gold nanorods (MSNs-AuNRs) that could reliably achieve a robust photothermal effect in response to second near-infrared (NIR-II) irradiation. To test the potential anti-Parkinsonian activity, we loaded MSNs-AuNRs with the frequently utilized anti-PD agent quercetin (QCT) to yield MSNs-AuNRs@QCT. Following NIR-II irradiation, we observed a dramatical increase in QCT transfer through the BBB, indicating that MSNs-AuNRs may enhance BBB permeability via the photothermal effect. These findings were further supported by rat pharmacokinetic studies, which clearly revealed that the combination of MSNs-AuNRs and NIR-II irradiation was associated with significantly improved brain accumulation. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine model of PD, we also found that intravenous MSNs-AuNRs@QCT delivery and subsequent NIR-II irradiation was sufficient to markedly reduce the neurological abnormalities in these mice. Together, this combination offers promising potential as a nanoplatform for neuroprotective drug delivery and treatment of PD.

Simultaneous quantification of vortioxetine, fluoxetine and their metabolites in rat plasma by UPLC-MS/MS.

In this study, a specific and quick ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was fully developed and validated for simultaneous measurement of the rat plasma levels of vortioxetine (VOR), Lu AA34443 (the major metabolite of VOR), fluoxetine and its metabolite norfluoxetine with diazepam as the internal standard (IS). After a simple protein precipitation with acetonitrile for sample preparation, the separation of the analytes were performed on an Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 μm) column, with acetonitrile and 0.1% formic acid in water as mobile phase by gradient elution. The detection was achieved on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via an electrospray ionization source. Good linearity was observed in the calibration curve for each analyte. The data of precision, accuracy, matrix effect, recovery and stability all conformed to the bioanalytical method validation of acceptance criteria of US Food and Drug Administration recommendations. The newly developed UPLC-MS/MS method allowed simultaneous quantification of VOR, fluoxetine and their metabolites for the first time and was successfully applied to a pharmacokinetic study in rats.

Quetiapine Fumarate Loaded Nanostructured Lipid Carrier for Enhancing Oral Bioavailability: Design, Development and Pharmacokinetic Assessment.

The study aimed at developing and characterizing Nanostructured Lipid Carriers (NLC) of Quetiapine Fumarate (QF) by Design of Experiment (DoE) for the enhancement of bioavailability. QF, an anti-psychotic drug, has an oral bioavailability of 9% due to hepatic first- pass metabolism necessitating the use of high doses. Its side effects are dose -related and enhancement in bioavailability would result in minimization of side effects. The objective of the study was the enhancement of bioavailability of the NLC of QF by preferential lymphatic uptake. Hot emulsification-ultrasonication was the method of formulation using PrecirolATO5 and Oleic acid as solid and liquid lipids respectively. Poloxamer188 and Phospholipon90G were used as surfactant and stabilizer respectively. Solid:liquid lipid ratio and Phospholipon90G amount were independent variables and percent Entrapment Efficiency (%EE), Particle Size (PS) dependent variables during optimization by Central Composite Design. The optimized formulation showed a %EE of 77.21%, PS of 140.2 nm and surface charge of - 19.9mV. Higuchi kinetic model was followed during the in-vitro release. TEM revealed spherical, smooth nanoparticles. A pharmacokinetic study in rats showed AUC0-∞ of QF-NLC to be 3.93 times that of QF in suspension, suggesting significant enhancement in bioavailability. An increase in AUC0-∞ in cycloheximide untreated rats' group of QF-NLC by 2.43 times as compared to cycloheximide treated group, confirmed lymphatic absorption of QF- NLC. The results validated DoE as an appropriate tool for developing QF loaded NLC and proved NLC to be a promising delivery system for the enhancement of oral bioavailability of QF.