Pharmacokinetic Behavior Research Articles

Glomerular Filtration Rate Measurement Utilizing Transdermal Detection Methodology.

The well-known accuracy limitations of estimated GFR (eGFR) currently employed in clinical practice present barriers to optimal care for patients with, or at-risk for, decreased kidney function. A point-of-care glomerular filtration rate (GFR) measurement methodology has the potential to address these limitations. We prospectively assessed transdermal detection of the novel fluorescent GFR tracer agent relmapirazin in participants having normal or impaired kidney function across all human skin colors on the Fitzpatrick Skin Scale (FSS). A multi-center study comprising 74 participants with eGFR from normal to Stage 4 CKD was performed. Forty-six participants were FSS types I-III, and twenty-eight were FSS type IV-VI. A module containing an LED and photodetector to activate and collect transdermal relmapirazin fluorescence was attached adhesively to the upper chest of each participant. Relmapirazin (1.5mg/kg) was administered by intravenous push, and fluorescence emission was acquired for 12 hours. A two-compartment pharmacokinetic model fit the fluorescent intensity vs time data, and the fluorescence clearance rate (FCR) was extracted from the second (terminal) compartment. Plasma relmapirazin concentrations were measured contemporaneously and the corresponding plasma GFR for each participant was determined. Linear regression analysis was used to compare the FCR to the indexed plasma GFR. Participant age range was 23 to 80 years old, with 59% females. The two-compartment pharmacokinetic behavior was observed in the fluorescence intensity vs time data and a FCR was successfully deduced for every participant completing the 12-hour study. The FCR vs. the indexed plasma GFR yielded an excellent correlation over the range of GFR measured and for all skin colors with a r2 = 0.90 (95% confidence interval 0.85 to 0.94). No severe adverse events were reported. Point-of-care transdermal detection of the fluorescent GFR tracer agent relmapirazin was feasible in patients with normal to impaired kidney function and for a range of skin color types.

Residual and pharmacokinetic behavior of berberine in Carassius auratus under intraperitoneal injection conditions by HPLC-Q-TOF/MS

Residual and pharmacokinetic behavior of berberine in Carassius auratus under intraperitoneal injection conditions by HPLC-Q-TOF/MS

Pharmacokinetics Integrated With Network Pharmacology to Investigate the Potential Mechanism of Lu-Jiao Fang Inhibited Endothelial-to-Mesenchymal Transition in Pressure Overload-Induced Cardiac Fibrosis.

The aim of this study was to investigate the potential mechanism of Lu-Jiao Fang (LJF) inhibiting endothelial-to-mesenchymal transition (EndMT) in pressure overload-induced cardiac fibrosis. Pharmacokinetic behaviors of the ingredients of LJF were evaluated by LC-MS/MS analysis. Then putative pathways by which LJF regulates EndMT were analyzed by network pharmacology and verified in transverse aortic constriction-induced cardiac fibrosis rats. Loganin, morroniside, salidroside, isopsoralen, and psoralen showed higher plasma, left and right ventricular Cmax and AUC0-t values than hesperidin, specnuezhenide, and icariside II. Twenty-four potential targets related to EndMT were identified, which were mainly involved in relaxin signaling pathway. AKT1, TP53, MMP9, HIF1A, Snail1, and MMP2 were key therapeutic targets in protein-protein interaction network. LJF reversed cardiac dysfunction, left ventricular dilation, and fibrosis and significantly downregulated collagen type I and III and EndMT regulators (Snail1 and Twist1) mRNA expression. In relaxin signaling pathway, the RXFP1 protein expression increased by 22.52%, and the protein phosphorylation of Smad2 and Smad3 decreased by 33.52% and 12.79%, in response to the treatment with LJF. This study initially revealed the EndMT inhibition effects and molecular mechanisms of LJF in cardiac fibrosis, providing a reference basis for the promotion of LJF in the clinic.

An insight into cancer nanomedicine based on polysaccharides.

With cancer rates on the rise around the world, cancer treatment has dominated scientific discussions in recent years. The toxicity of cytotoxic drugs, their lack of tumor localization, and their uniform dispersion into tumor tissues are the obstacles to cancer therapy. Other cancer treatment drawbacks include short blood circulation half-lives and undesirable pharmacokinetic behavior. Low-molecular-weight drugs conjugated with macromolecular carriers are better distributed in the body. The enhanced permeation and retention (EPR) effect causes natural and synthetic polymers, such as polysaccharides, proteins, antibodies, and poly amino acids, to accumulate in tumor tissue. Many manufactured and natural polymers are attractive polymeric drug carriers, allowing the creation of prodrugs from medicinal substances. Polysaccharides are biological polymers with structural and functional variations. They are also non-toxic, hydrophilic, biodegradable, and efficiently bioactive. Polysaccharides are ideal for synthesizing many nanoparticles due to their functional groups. Their ability to adapt to their microenvironment makes them valuable. Nanoplatforms based on polysaccharides can deliver targeted anticancer drugs for personalized cancer treatment. Unique polysaccharide structures and properties offer chemical and biological advantages for novel drug delivery. Polysaccharide-drug conjugation could revolutionize cancer chemotherapy. This study investigates polysaccharide conjugates and polysaccharides as natural biomaterials for cancer drug delivery.

Unraveling the in vivo pharmacokinetic behavior of mPEG5-NH2 polymer in rats by UHPLC-MS/MS assay.

As an important chemical reagent, methoxy polyethylene glycol amine (mPEG-NH2) is widely used in biomedical field. Unraveling the pharmacokinetic behavior of mPEG-NH2 polymers is essential for revealing the toxicity and efficiency of mPEG-NH2 related drug delivery systems. In this study, a simple analytical assay based on mass spectrometry (MS) was first established and validated for quantification of mPEG5-NH2 in biological matrix. The multiple reaction monitoring (MRM) transitions at m/z 252.2 (precursor ions)→87.7 (fragment ions) and m/z 371.2 (precursor ions)→89.2 (fragment ions) were chosen to determine mPEG5-NH2 and OH-PEG8-OH, respectively. The UHPLC-MS/MS assay showed excellent linearity over the range of 0.01-10μg/mL. Intra-day and inter-day accuracies and precisions of the assay were all within±6.44%. The analytical assay was successfully applied to reveal the in vivo pharmacokinetic behavior of mPEG5-NH2 in rats.

Exploration of Enalapril-Lacidipine Co-Amorphous System with Superior Dissolution, In vivo Absorption and Physical Stability via Incorporated into Mesoporous Silica.

In the present study, enalapril (ENP) was taking as a potential co-former to fabricate co-amorphous system with lacidipine (LCDP). The ENP/LCDP co-amorphous system was firstly prepared with or without mesoporous SiO2 and characterized by DSC, XRD and SEM technologies. The potential molecular interactions were evaluated by FTIR spectrums. Furthermore, the dissolution and pharmacokinetics behavior of various formulations were also carried out. It was demonstrated that the completely co-amorphization was obtained at ENP/LCDP 2:1 molar ratio by the intermolecular interactions between ENP and LCDP. The ENP/LCDP co-amorphous system significantly improve the dissolution rate of LCDP and ENP respectively. Compared to the naked ENP/LCDP co-amorphous system, remarkable enhancement of dissolution rate and bioavailability of model drugs was observed by incorporated the co-amorphous system into mesoporous SiO2, and a superior physical stability was also observed after accelerated study. Raman mapping revealed that the less microstructure phase separation could be the main reason for the better stability in presence of mesoporous SiO2. In conclusion, ENP could be successfully used as a potential co-former to fabricate co-amorphous system with poorly water-soluble drugs and collaborates the co-amorphous with mesoporous SiO2 become a promising strategy to achieve stable amorphous formulation for further enhancement of dissolution rate and bioavailability.

Dissolution and Pharmacokinetic Studies of Paracetamol-4,4′-Bipyridine Cocrystals Obtained Using Four Methods

Paracetamol-4,4′-bipyridine cocrystals were synthesized using a solution method, reflux method, grinding method, and ultrasonic method. The structures and properties were characterized through the utilization of single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), polarized light microscopy (PLM), thermogravimetric analysis (TGA), elemental analysis (EA), and infrared spectroscopy (IR). The results show that the four methods synthesized different cocrystal morphologies, but the same structure and properties coupled with a notably high purity level. All featured strong hydrogen bonds formed between the paracetamol,4,4′-bipyridine and water molecules. An additional notable feature is the presence of π...π stacking interactions between the pyridine rings of adjacent 4,4′-bipyridine molecules. The solubility of paracetamol (active pharmaceutical ingredient, API) and the cocrystal was measured and discussed. In the dissolution experiment, the cocrystal showed a much faster dissolution rate than the API in simulated gastric fluid media (pH = 1.2). Furthermore, the pharmacokinetic (PK) behavior of the cocrystal and the API was investigated to evaluate the effectiveness of this strategy for enhancing the oral absorption of paracetamol. The in vitro and in vivo studies revealed that the paracetamol-4,4′-bipyridine cocrystal possessed an excellent dissolution behavior and an improved pharmacokinetic profile.

Pharmacophore Optimization using Pharmacophore Mapping, QSAR, Docking, and ADMET Screening of Novel Pyrimidines Derivatives as Anticancer DNA Inhibitors

Cancer is a global health issue, and cancer cells' resistance to existing treatments has prompted a search for new anticancer drugs. The DNA of cancer cells is regarded as the primary target for developing new molecules. In-silico studies aid in the optimization of current pharmacophores and the development of new molecules. This study aimed to optimize the pharmacophore utilizing QSAR studies and pharmacophore mapping to generate novel chemical entities (NCEs) of pyrimidine derivatives as DNA inhibitors for cancer treatment. Furthermore, these NCEs were subjected to molecular docking and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening to determine their drug-likeness. This study used Schrodinger's Maestro (13.4) software for pharmacophore mapping, QSAR, molecular docking, and ADME. Toxicity was determined using the Pro Tox II online tool. Pharmacophore mapping was performed using the phase module. The QSAR model was generated using an atom-based QSAR approach. The Qik prop module was utilized for ADME prediction. Molecular docking was done in Standard precision mode. In pharmacophore mapping, we discovered that the DHHRR_1 hypothesis fitted best, with a survival score of 5.4408. The optimal atom-based QSAR model produced correlation coefficients of R<sup>2</sup> = 0.9487 and Q<sup>2</sup> = 0.8361. Based on QSAR research, a new set of 43 derivatives was generated. These compounds pass all ADMET requirements. In molecular docking investigations, three compounds demonstrated binding with key amino acids with a significant dock score comparable to the standard. Considering docking data and pharmacokinetic behavior of newly developed compounds, molecules NC10, NC9, and NC43 have the highest DNA binding capability.

Liquid Chromatography‐Tandem Mass Spectrometry Analysis and Pharmacokinetics of Doxorubicin and Its Prodrug in Rats After Administration of Nanoparticles

ABSTRACTTo further improve the dilemma facing the clinical application of doxorubicin (DOX), we designed a cathepsin B sensitive DOX prodrug albumin nanoparticle (NP). To evaluate the pharmacokinetics of prodrug albumin NPs (C16‐GFLG‐PAB‐DOX NPs), we developed and validated a liquid chromatography‐tandem mass spectrometry method for the same time analysis of DOX and its fatty acid prodrug (C16‐GFLG‐PAB‐DOX) in rat plasma. The method uses the precipitated protein method to extract analytes from rat plasma. The validated method on selectivity, linearity (r ≥ 0.992), precision (relative standard deviation: 3.5%–9.5%), accuracy (relative error: −2.9% to 3.5%), extraction recovery (80.2% to 90.4%), matrix effect (87.8% to 96.6%), and stability in different conditions were satisfied. Therefore, the pharmacokinetic behavior of C16‐GFLG‐PAB‐DOX NPs in rats was investigated using this analytical approach. The outcome of the pharmacokinetic study illustrated that prodrug albumin NPs are promising to alleviate the problems associated with DOX in clinical applications.

Mass Spectrometric Based Metabolomics of the Saudi Cultivar of Fenugreek (Trigonella foenum-graecum L.): A Combined GC-MS, Antimicrobial and Computational Approach.

Background and Objective: In Saudi Arabia, numerous plant species with promising medicinal properties are cultivated, widely traded, and commonly utilized in traditional medicine, including fenugreek (Trigonella foenum-graecum). This study aimed to comprehensively assess the phytochemical composition and antimicrobial potential of the Saudi cultivar of fenugreek using an integrative approach combining in vitro and in silico methodologies. Methods: A comprehensive investigation was conducted on the ethanol extract of fenugreek seeds, assessing its antibacterial, antifungal, properties. Computational modeling was employed to predict pharmacokinetic behavior and potential toxicity of the identified bioactive compounds. Results: Qalitative phytochemical analysis showed presence of alkaloids, tannins, saponins, glycosides, flavonoids, and steroids, while terpenoids were notably absent. GC-MS analysis of Trigonella foenum-graecum (fenugreek) seeds identified 25 bioactive compounds, with Ethyl methane sulfonate (12.41%) being the predominant component. Other key compounds included n-Hexadecanoic acid, 4-Butyl-2(4-nitrophenyl)-1,3-thiazole, and α-Tocopherol. In silico modeling of fenugreek phytochemicals supported their antibacterial, antioxidant, and neuroprotective potential, with compounds 21 and 24 showing strong binding to key targets like Tyrosyl-tRNA Synthetase (TyrRS) of Staphylococcus aureus (S. aureus), Aspartic proteinase from Candida albicans (C. albicans) and human peroxiredoxin 5. Pharmacokinetic analysis indicated good oral bioavailability, minimal CYP inhibition, and blood-brain barrier penetration, suggesting potential for treating neurodegenerative diseases. These bioactive compounds, including diosgenin and trigonelline, support fenugreek's therapeutic promise and warrant further in vitro, in vivo, and clinical studies. Conclusion: The Saudi fenugreek cultivar is rich in bioactive compounds with good antibacterial potential. These findings establish a robust foundation for continued pharmacological research on the Saudi cultivar of T. foenum-graecum, highlighting its potential as a rich source of bioactive compounds with significant medicinal value.

Inhibiting De Novo Biosynthesis of Ceramide by L-Cycloserine Can Prevent Light-Induced Retinal Degeneration in Albino BALB/c Mice.

Retinal degenerative diseases lead to irreversible vision loss due to photoreceptor cell death, driven by complex genetic and environmental factors. Ceramide, a sphingolipid metabolite, emerges as a critical mediator in the apoptotic cascade associated with retinal degeneration. Our previous work demonstrated L-Cycloserine's ability to protect photoreceptor-derived cells from oxidative stress by inhibiting the de novo ceramide pathway and thus prompting further investigation on its effect in the in vivo retina. This study investigates the potential of L-Cycloserine to protect albino BALB/c mice against light-induced retinal degeneration (LIRD). L-Cycloserine, in an optimal dose, administered systemically 30 min before LIRD, was found to prevent photoreceptor cell death significantly from light-induced degeneration. We further determined the retinal bioavailability and pharmacokinetic behavior of L-Cycloserine, its effect on sphingolipid profile, expression of sphingolipid biosynthetic, and cell death-promoting genes and proteins from the retina to understand the underlying mechanisms. This study lays the groundwork for further preclinical and clinical investigations into L-Cycloserine's potential as a novel therapeutic in treating retinal degenerative diseases.

Essential oil constituents of regional ethnomedicinal plants as potential inhibitors of SARS-CoV-2 Mpro: an integrated molecular docking, molecular dynamics and QM/MM study

The scientific community has achieved a remarkable milestone by creating efficacious vaccines against the SARS-CoV-2 virus. The treatment alternatives are still restricted, though. The bioactive ingredients present in natural plants are known to exhibit diverse pharmacological effects against many diseases. Using computational techniques such as molecular docking, drug-likeness, ADMET study, MD simulation, and our own N-layered Integrated molecular Orbital and Molecular mechanics (ONIOM) calculations, this study aimed to investigate essential oil constituents of Lindera neesiana, Litsea cubeba and Zanthoxylum armatum DC plants as a potential natural inhibitor of SARS-CoV-2 main protease (Mpro). To determine their binding affinity, 107 phytochemical substances in total were docked inside the binding pocket of Mpro. Copaene showed the highest binding affinity among the 107 compounds, with an energy of −7.90 kcal/mol. Furthermore, physiochemical and ADMET properties were evaluated for the top five phytocompounds. The studied phytocompounds showed good physiochemical and pharmacokinetic behaviour with no associated toxicity. MD simulation further provided evidence for stable interaction of phytocompounds within the binding pocket of Mpro. Subsequently, ONIOM calculation was done on the best-hit complex, wherein the hydrogen bonding interactions were retained with appreciable negative energy. These in silico results indicate that the specific phytocompounds present in essential oils of L. neesiana, L. cubeba, and Z. armatum DC have significant inhibitor ability against SARS-CoV-2 main protease and could be explored for future therapeutic investigations.

Nano - Based Therapeutic Strategies in Management of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, progressively distinctive via cartilage destruction, auto-antibody production, severe joint pain, and synovial inflammation. Nanotechnology represents as one of the utmost promising scientific technologies of the 21st century. It exhibits remarkable potential in the field of medicine, including imaging techniques and diagnostic tools, drug delivery systems and providing advances in treatment of several diseases with nanosized structures (less than 100 nm). Conventional drugs as a cornerstone of RA management including disease-modifying antirheumatic drugs (DMARDS), Glucocorticosteroids, etc are under clinical practice. Nevertheless, their low solubility profile, poor pharmacokinetics behaviour, and non-targeted distribution not only hamper their effectiveness, but also give rise to severe adverse effects which leads to the need for the emergence of nanoscale drug delivery systems. Several types of nano-diagnostic agents and nanocarriers have been identified; including polymeric nanoparticles (NPs), liposomes, nanogels, metallic NPs, nanofibres, carbon nanotubes, nano fullerene etc. Various patents and clinical trial data have been reported in relevance to RA treatment. Nanocarriers, unlike standard medications, encapsulate molecules with high drug loading efficacy and avoid drug leakage and burst release before reaching the inflamed sites. Because of its enhanced targeting specificity with the ability to solubilise hydrophobic drugs, it acts as an enhanced drug delivery system. This study explores nanoparticles potential role in RA as a carrier for site-specific delivery and its promising strategies to overcome the drawbacks. Hence, it concludes that nanomedicine is advantageous compared with conventional therapy to enhanced futuristic approach.

Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment

Background/Objectives: Etrasimod is a newly FDA-approved Sphingosine-1-Phosphate modulator indicated for moderate and severe ulcerative colitis. It is extensively metabolized in the liver via the cytochrome P450 system and may accumulate markedly in patients with hepatic dysfunction, exposing them to toxicity. The aim of the current study is to utilize a physiologically-based pharmacokinetic modeling approach to evaluate the impact of hepatic impairment on the pharmacokinetic behavior of etrasimod and to appropriately select dosage regimens for patients with chronic liver disease; Methods: PK-Sim was used to develop the etrasimod PBPK model, which was verified using clinical data from healthy subjects and subsequently adapted to reflect the physiological changes associated with varying degrees of hepatic dysfunction; Results: Simulations indicated that hepatic clearance of etrasimod is clearly reduced in patients with Child–Pugh B and C liver impairment. Based on these findings, dosing adjustments were proposed to achieve therapeutic exposures equivalent to those in individuals with normal liver function. In the Child–Pugh B and C population groups, 75% and 62.5%, respectively, of the standard dose were enough to have comparable exposure to the healthy population. These adjusted dosages aim to mitigate the risk of drug toxicity while maintaining efficacy; Conclusions: The PBPK model provides a robust framework for individualizing drug therapy in patients with hepatic impairment, ensuring safer and more effective treatment outcomes. Further clinical studies are warranted to verify these dosing recommendations and to refine the model for broader clinical applications.

Spanlastic Nano-Vesicles: A Novel Approach to Improve the Dissolution, Bioavailability, and Pharmacokinetic Behavior of Famotidine.

Background/Objectives: Drugs exhibiting poor aqueous solubility present a challenge to efficient delivery to the site of action. Spanlastics (a nano, surfactant-based drug delivery system) have emerged as a powerful tool to improve solubility, bioavailability, and delivery to the site of action. This study aimed to better understand factors affecting the physicochemical properties of spanlastics, quantify their effects, and use them to enhance the bioavailability of famotidine (FMT), a model histamine H2 receptor antagonist (BCS class IV). Methods: FMT was incorporated into nano-spanlastics drug delivery system. The ethanol injection method, Box-Behnken design, and mathematical modeling were utilized to fabricate famotidine-loaded nano-spanlastics and optimize the formula. Spanlastics were characterized for their particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, compatibility of the excipients (using DSC), in vitro drug release, and in vivo pharmacokinetics. Results: Span 60 (the non-ionic surfactant) and tween 60 (the edge activator) gave rise to spanlastics with the best characteristics. The optimal spanlastic formulation exhibited small particle size (<200 nm), appropriate polydispersity index (<0.4), and zeta potential (>-30 mV). The entrapment efficiency and drug loading of the optimum formula assured its suitability for hydrophobic drug entrapment as well as practicability for use. DSC assured the compatibility of all formulation components. The drug release manifested a biphasic release pattern, resulting in a fast onset and sustained effect. Spanlastics also showed enhanced Cmax, AUC0-24, and bioavailability. Conclusions: Spanlastics manifested improved FMT dissolution, drug release characteristics, membrane permeation, and pharmacokinetic behavior.

Pharmacokinetics and Bioequivalence Evaluation of Trazodone Hydrochloride Sustained-Release Tablets in Healthy Chinese Volunteers.

The aim of this study was to investigate the pharmacokinetics, bioequivalence, and safety of generic trazodone hydrochloride sustained-release tablet and its reference listed product in healthy Chinese subjects. An open, randomized, single-dose, and 2-period crossover study was involved under fasting and fed conditions, with a 7-day washout period. A single oral dose of 150mg of 2 trazodone hydrochloride sustained-release tablets was administered to 84 healthy volunteers, with 36 in the fasting group and 48 consuming a high-fat diet, respectively. The plasma concentrations of trazodone were analyzed using a liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters were obtained from concentration-time profiles. The geometric mean ratio with 90% confidence intervals of the maximum trazodone concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were within the bioequivalence acceptance criteria (80%-125%) under fasting and fed conditions, which indicated that the test and reference formulations were bioequivalent. Compared with the fasting study, the concomitant administration of trazodone with a high-fat diet had a negligible influence on the drug pharmacokinetic behavior. Adverse events were recorded, and no serious adverse events were observed during either fasting or fed conditions. Trazodone has proven to have an acceptable safety profile in the Chinese population, with bioequivalence successfully established under both fasting and fed conditions.

Analysis of Herbal Constituents and InVivo Pharmacokinetics of Gegen-Huangqi Decoction in Rat Plasma Using HPLC-Q-TOF-MS/MS and HPLC-QQQ-MS/MS.

The traditional Chinese medicine (TCM) formula, gegen-huangqi (GH) decoction, has been employed for over 200 years, notably for its therapeutic effects in treating conditions such as atherosclerosis and diabetes mellitus. Despite its long-standing use, comprehensive studies on the chemical constituents of GH and their invivo pharmacokinetics (PK) remain limited. This study aimed to profile the bioactive compounds present in GH decoction and to explore their PK characteristics using HPLC-Q-TOF-MS/MS. Furthermore, a robust and validated analytical method was developed and applied to assess the PK of 11 plasma compounds using HPLC-QQQ-MS/MS. In total, 79 components were identified within the GH decoction. Pharmacokinetic analysis revealed distinct absorption and elimination profiles for compounds such as puerarin, daidzin, genistin, calycosin-7-O-β-D-glucoside, and ononin, which exhibited profiles of quick absorption and excretion. Conversely, compounds such as daidzein, formononetin, genistein, astragaloside II, astragaloside IV, and calycosin showed more complex invivo metabolic patterns, leading to multipeak concentration-time curves. All compounds, except astragalosides II and IV, were found to undergo significant hepatic clearance. These findings provide valuable insights into the pharmacokinetic behavior of GH decoction, which lays the foundation for further quality control, pharmacological exploration, and potential clinical application of this traditional remedy.

Pharmacokinetics and Quantitative Structure-Pharmacokinetics Relationship Study of Xanthine Derivatives with Antidepressant, Anti-Inflammatory, and Analgesic Activity in Rats.

The aim of this study was to develop quantitative structure-pharmacokinetics relationship (QSPKR) models for a group of xanthine derivatives with proven pharmacological activity and to investigate its applicability for the prediction of the pharmacokinetics of these compounds. The SYBYL-X, KowWin, and MarvinSketch programs were employed to generate a total of fourteen descriptor variables for a series of new compounds: 7- and 7,8-substituted theophylline derivatives (GR-1-GR-8) and three well-known methylxanthines. Pharmacokinetic profiles of all compounds were determined after intravenous administration of studied compounds to cannulated male rats. Pharmacokinetic parameters were calculated using noncompartmental analysis. Multiple linear regression revealed that logD was the main determinant of the variability in Vss, λz, and CL of the studied compounds. Moreover, λz and CL depended on LUMO and HEFO, while for Vz COAR was the only explanatory variable. The developed QSPKR models accounted for most of the variation in Vss, λz, CL, and fraction unbound (fu) (R2 ranged from 0.68 to 0.91). Cross-validation confirmed the predictive ability of the models (Q2 = 0.60, 0.71, 0.34, and 0.32 for Vss, λz, CL, and fu, respectively). The multivariate QSPKR models developed in this study adequately predicted the overall pharmacokinetic behavior of xanthine derivatives in rats.

Comparative Pharmacokinetic Assessment of Curcumin in Rats Following Intratracheal Instillation Versus Oral Administration: Concurrent Detection of Curcumin and Its Conjugates in Plasma by LC-MS/MS.

To establish and validate an LC-MS/MS method for the simultaneous determination of curcumin (CUR) as well as its glucuronide conjugate (COG) and sulfate conjugate (COS) in rat plasma. The method was employed to evaluate and compare the pharmacokinetic behaviors of curcumin following oral and intratracheal administration in rats. Rat plasma samples were separated by chromatography on a C18 column after protein precipitation with acetonitrile. Gradient elution with a mobile phase of 0.5 mM ammonium acetate in acetonitrile was utilized. Mass spectrometry detection incorporated an electrospray ionization (ESI) source, multiple reaction monitoring (MRM), and dual-mode (positive and negative) scanning for quantitative analysis. A total of 12 SD rats were randomly divided into two groups and were orally (20 mg/kg) or intratracheally (10 mg/kg) administrated curcumin, respectively. CUR, COG, and COS concentrations in plasma were measured to assess pharmacokinetic disparities. The method demonstrated linearity within the ranges of 2-400 ng/mL for CUR and COS and 5-1000 ng/mL for COG. Intratracheal administration significantly elevated CUR plasma concentrations compared to oral administration. The exposure of COG was higher than COS following oral administration. Conversely, intratracheal administration resulted in markedly higher COS exposure, with no significant difference in COG exposure after dose normalization between oral and inhalation routes. The established LC-MS/MS method provides a reliable tool for the simultaneous measurement of CUR, COG, and COS in rat plasma, facilitating preclinical pharmacokinetic investigations. The study reveals distinct pharmacokinetic profiles for CUR following oral versus intratracheal administration, suggesting that inhalation may offer superior therapeutic efficacy.

Computer Modeling of Bevacizumab Drug Distribution After Intravitreal Injection in Rabbit and Human Eyes.

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action in the vitreous. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.