ADMET and DMPK最新文献

Background and purpose: The solubility of weakly-ionizable drugs in pure water, S_w, is commonly measured. The pH-dependent properties of the saturated solutions can be surprisingly complex in subtle ways. This commentary examines the characteristics of such measurements through case studies of 32 free acids, bases, and ampholytes (including crocetin, glibenclamide, mellitic acid, quercetin, bedaquiline, brigatinib, imatinib, celecoxib, and lysine), using published water solubility data.

Computational approach: Usually, in such saturated solutions, the ionic strength, I _w, is close to zero. When the pH is adjusted away from pH_w, the ionic strength increases, substantially in some cases (e.g. I _w > 10 M at pH 7.4 for mellitic acid and lysine). This change in ionic strength alters the activities of the species in solution. The corresponding equilibrium constants used to calculate the concentrations of these species must be adjusted accordingly. Here, the Stokes-Robinson hydration theory, slightly modified with Setschenow 'salting-out' constants to account for solvent interactions with unionized drugs, was used to estimate activity coefficients. The calculations were performed with the pDISOL-X program.

Key results: Given reliably-measured values of solubility in water (S _w) and ionization constant (pK _a) of the drugs and assuming that the Henderson-Hasselbalch equation is valid, a method is described for (i) adjusting the measured S _w values at ionic strength, I _w ~ 0 M, to values expected at reference ionic strength, I _ref = 0.15 M (or at any other reasonable reference value), (ii) determining the water pH_w in saturated solutions of added neutral-form drugs; (iii) determining the intrinsic solubility, S ₀, both at I _w and I _ref, and (iv) using analytic-continuation in the equilibrium mass action model to deduce the solubility values as a function of pH, harmonized to a selected I _ref. For highly soluble drugs, whose I _w exceeds 0.15 M, the intrinsic solubility values appear to depend on the amount of excess solid added.

Conclusion: This commentary re-emphasizes that measured S _w is not generally the same as S ₀. It is stressed that transforming measured drug solubility in pure water to an ionic strength level that is physiologically appropriate would better match the conditions found in biological media, potentially improving applications of solubility in pharmaceutical research and development.

Background and purpose: Sumatriptan is used to alleviate symptoms of migraine headaches, particularly during acute attacks. Naproxen is a medication that provides relief from pain, inflammation, and fever. Therefore, determination of them is important.

Experimental approach: In the present work, CoMoO₄ nanosheets were synthesized in a basic and easy way. A screen-printed graphite electrode's surface was altered using the as-prepared CoMoO₄ nanosheets' high electroactivity to create a CoMoO₄ nanosheets-modified screen-printed electrode (CoMoO₄ NSs-SPE), which was then employed for sumatriptan's electrochemical oxidation. Due to the superior electron transfer characteristics and catalytic activity of the produced CoMoO₄ nanosheets, the results demonstrated a notable improvement in sumatriptan's current responses. This study examined the electrochemical behavior of sumatriptan on the CoMoO₄ NSs-SPE utilizing a number of methods, including as chronoamperometry, cyclic voltammetry, and differential pulse voltammetry (DPV).

Key results: With a high sensitivity of 0.0718 μA/μM and a good correlation value of 0.9998, a linear calibration curve was obtained over a broad concentration range of 0.02-600.0 μM, suggesting a strong linear connection between the concentration and the response. Based on a signal-to-noise ratio of 3, the limit of detection for sumatriptan was determined to be 0.01 μM, suggesting a high degree of sensitivity for the detection technique. DPV results showed that the CoMoO₄ nanosheets-modified screen-printed electrode (CoMoO₄ NSs-SPE) could detect naproxen and sumatriptan at the same time.

Conclusion: The created sensor's usefulness and efficacy in real-world applications were demonstrated when it was successfully used to identify the target analytes in actual samples.

Background and purpose: This study aimed to explore the modification of screen-printed carbon electrode (SPCE) to produce an extensive conductive surface with gold nanoparticles (AuNPs) for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ribonucleic acid (RNA).

Experimental approach: The experiment was carried out using drop casting (DC) and spray coating (SC) methods. Au-S covalent interactions were formed between thiolated single-stranded DNA (ssDNA) and Au surface, which further hybridized with the target RNA to be detected using differential pulse voltammetry (DPV). Optimization of experimental conditions was performed using Box-Behnken design (BBD) on probe ssDNA concentration, probe ssDNA immobilization time, and target hybridization time. The morphology of the modified electrode was characterized using a scanning electron microscope, while the electrochemical behaviour was determined with DPV and electron impedance spectroscopy.

Key results: The results showed that SPCE modification with AuNPs by DC produced a higher peak current height of 12.267 μA with an R _ct value of 2.534 kΩ, while SC improved the distribution of AuNPs in the electrode surface. The optimum experimental conditions obtained using BBD were 0.5 μg mL^-1 ssDNA-probe concentration, an immobilization time of 22 minutes, and a hybridization time of 12 minutes. The limit of SARS-CoV-2 RNA detection at a concentration range of 0.5 to 10 μg mL^-1 was 0.1664 and 0.694 μg mL^-1 for DC and SC, respectively. The T-test results for both methods show that the current response of target RNA with SPCE/AuNP by DC does not show the same result, indicating a significant difference in the current response between those two methods.

Conclusion: SPCE/AuNP by DC is better than SPCE/AuNP by SC for immobilizing inosine-substituted ssDNA, which subsequently hybridizes with viral RNA, enabling label-free detection of guanine from SARS-CoV-2 RNA.

Background and purpose: Many new compounds are being prepared to overcome the problem of increasing microbial resistance and the increasing number of infections.

Experimental approach: This study includes a series of twenty-seven mono-, di- and trisubstituted 2-hydroxynaphthalene-1-carboxanilides designed as multitarget agents. The compounds are substituted with methoxy, methyl, and nitro groups, as well as additionally with chlorine, bromine, and trifluoromethyl at various positions. All the compounds were evaluated for antibacterial activities against Gram-positive and Gram-negative bacteria and mycobacteria. Cytotoxicity on human cells was also tested.

Key results: Three compounds showed activity comparable to clinically used drugs. N-(3,5-Dimethylphenyl)-2-hydroxynaphthalene-1-carboxamide (13) showed only antistaphylococcal activity (minimum inhibitory concentration (MIC) = 54.9 μM); 2-hydroxy-N-[2-methyl-5-(trifluoromethyl)phenyl]naphthalene-1-carboxamide (22) and 2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide (27) were active across the entire spectrum of tested bacteria/mycobacteria, both against the sensitive set and against resistant isolates (MICs range 0.3 to 92.6 μM). Compound 22 was even active against E. coli (MIC = 23.2 μM). The active agents showed no in vitro cytotoxicity up to a concentration of 30 μM.

Conclusion: Compounds with trifluoromethyl in the meta-anilide position, experimental lipophilicity expressed as log k (logarithm of the capacity factor) in the range of 0.31 to 0.34 and calculated electron σ parameter for the anilide substituent higher than 0.59 were effective. The investigated compounds meet the definition of Michael acceptors. Based on ADME screening, the investigated compounds 13, 22 and 27 should have suitable physicochemical parameters for good bioavailability in the organism. Therefore, these are promising agents for further study.

Background and purpose: Dopamine has an impact on the cardiovascular, endocrine, renal, and central neurological systems. Electrochemical techniques are becoming more and more popular among researchers as a way to assess dopamine and uric acid levels.

Experimental approach: Using electrochemical techniques, a new Universitet i Oslo MOF (UiO-66)-graphene oxide nanocomposite-modified carbon paste electrode was created to investigate the electrooxidation of uric acid and dopamine as well as their combinations. At the redesigned electrode, uric acid and dopamine were detected concurrently in a very sensitive way using differential pulse voltammetry (DPV).

Key results: Dopamine DPV peak currents increase in a linear fashion at doses between 0.05 and 600.0 μM.

Conclusion: Uric acid and dopamine levels in urine and dopamine injection samples may be determined with the help of the proposed sensor, which is reasonably priced and performs well.

Background and purpose: Cardiac mitochondria dysfunction plays a central pathophysiological role in the abnormal glucose metabolism in the heart during diabetic cardiomyopathy. The present study evaluated the effects of flavonoid glycoside naringin treatment on the interconnection between changes in cardiac mitochondria oxygen consumption, membrane potential and mitochondrial Ca²⁺ sensitivity during type 1 diabetes.

Experimental approach: Type 1 diabetes was induced by an intraperitoneal injection of streptozotocin (40 mg/kg) in rats and islet morphology, glucose and insulin levels, changes in heart mitochondria respiration, membrane potential, spontaneous and Ca²⁺ - induced mitochondrial permeability transition (MPT) pore opening were evaluated.

Key results: Diabetes resulted in typical signs of hyperglycaemia, which were accompanied by a rat cardiac mitochondria dysfunction, manifested by decreased V ₂ and V ₃ rates of oxygen consumption, while the initial membrane potential value remained unchanged. The rates of Ca²⁺-induced MPT pore opening and Ca²⁺-induced membrane potential dissipation in isolated mitochondria decreased under type 1 diabetes. The naringin treatment (40 mg/kg of the body weight, 4 weeks) partially recovered impaired cardiac mitochondria respiration, decreased spontaneous and increased Ca²⁺-induced MPT pore opening, improved pancreatic islets morphology and dystrophic changes, lowered glycated haemoglobin and blood plasma urea, and decreased the oxidative stress level with glucose or insulin concentrations remaining unchanged in diabetic animals.

Conclusions: Naringin administration demonstrated beneficial effects during type 1 diabetes and represents a promising therapeutic (or nutraceutical) approach for diabetes treatment.

Background and purpose: Cancer is a serious public health concern, hence the determination of dacarbazine as a significant chemotherapeutic agent is very important.

Experimental approach: In the present work, we use a facile method to synthesize a nanocomposite of multi-walled carbon nanotubes (MWCNTs) and two-dimensional zeolitic imidazolate framework nanosheets (2D ZIF-L NSs). The resulting MWCNTs/2D ZIF-L NSs nanocomposite was characterized by field-emission scanning electron microscopy. The MWCNTs/2D ZIF-L NSs nanocomposite was subsequently used to modify a screen-printed carbon electrode (SPCE) to achieve an electrochemical sensing platform for the detection of dacarbazine.

Key results: From cyclic voltammetric studies, it was found that the MWCNTs/2D ZIF-L NSs nanocomposite modified SPCE provided less anodic peak potential (700 mV) and higher anodic peak current (7.7 μA) for oxidation of dacarbazine when compared to other SPCEs. The MWCNTs/2D ZIF-L NSs/SPCE displayed good performance in the quantitative determination of dacarbazine. Under optimum conditions, the differential pulse voltammetry response exhibited a linear concentration range of 0.01 to 80.0 μM for dacarbazine with a relatively high sensitivity of 0.1384 μA μM^-1 and an estimated detection limit of 0.004 μM. The MWCNTs/2D ZIF-L NSs/SPCE sensor was also successfully applied to the determination of dacarbazine in injections samples of dacarbazine.

Conclusion: This detection method can be used as a valuable tool in the analysis of pharmaceutical formulations to bring benefits in cancer treatment.

Background and purpose: Urate crystal accumulation may lead to the condition of ocular tophaceous gout, causing ocular inflammation and increased intraocular pressure (IOP) due to the triggering of several inflammatory receptors like NLRP3, A2A, and TLR4. The study has been undertaken to manage intraocular pressure and inflammation using febuxostat (FBX) film formulation for sustained and improved activity, particularly for long-term tophaceous gout patients.

Experimental approach: Hydroxypropyl methylcellulose K100 matrix-based hydrogel film of FBX has been fabricated in the presence of plasticizers like triethanolamine, dimethyl-sulphoxide (DMSO), or polyethylene glycol 600 using casting and evaporation technique. Carrageenan was injected into the upper palpebral region to induce ocular inflammation, and a normotensive rabbit eye model was used for monitoring IOP.

Key results: Amorphization of the drug was observed from the differential scanning calorimetry and X-ray diffraction results. In vitro release study revealed an improved and diffusion-controlled sustained drug release for more than 5 h (62.69 to 84.76 %). Compared to its absence, decreased IOP was extended up to 5 h using film (with DMSO). Disappearance of ocular inflammation was also observed in the test animals after 2.5 h of film application, whereas acute inflammation was continued in the group without treatment for more than 4 h. Docking study revealed good binding interaction of drug and NLRP3, A2A, and TLR4 receptor.

Conclusion: Febuxostat-loaded hydrogel-forming plasticized film could be utilized to better manage and control ocular inflammation and associated IOP, particularly in ocular tophaceous gout patients.

Introduction: Modafinil, a wakefulness-promoting agent, is primarily used to treat excessive daytime sleepiness associated with narcolepsy and fatigue. As a BCS class II drug, modafinil exhibits low solubility and high permeability, with its crystalline structure significantly impacting dissolution, bioavailability, and compressibility. This study explores the use of microwave energy to alter the crystalline structure of modafinil in the presence of Gelucire^® 48/16, aiming to improve its pharmaceutical properties.

Methods: Modafinil was treated with microwave energy to form complexes with Gelucire^® 48/16, and the resulting formulations were compared to hot-melt complexes and physical mixtures. The structural and thermal properties of the complexes were characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Compressibility and compactibility were evaluated through Kawakita model analysis and response surface methodology). The effect of microwaves on molecular interactions was further investigated using molecular modeling.

Results: XRPD analysis revealed distinct crystalline patterns for microwave and hot-melt complexes compared to physical mixtures, with increased amorphousness observed through crystallinity, relative crystallinity, and relative intensity parameters. DSC thermograms indicated a reduction in melting endotherms and heat flow, suggesting structural changes due to complex formation. Compressibility and compactibility studies demonstrated optimal performance at low Gelucire^® content, with microwave-treated complexes exhibiting superior properties to untreated mixtures. Molecular modeling confirmed dipole-dipole interactions between modafinil and the hydrophilic portion of Gelucire^®.

Conclusions: The study demonstrates that microwave energy effectively alters the crystalline structure of modafinil in the presence of Gelucire^® 48/16, enhancing its amorphousness, compressibility, and compatibility. These findings highlight the potential of microwave-assisted complexation as a novel approach to improve the pharmaceutical performance of BCS Class II drugs like modafinil.

Background and purpose: The pH value of the small intestine is physiologically maintained by bicarbonate buffer (BCB). However, the effect of BCB on the membrane permeation of drugs has not been investigated. The purpose of this study was to investigate the effect of BCB on the passive membrane permeation of drugs.

Experimental approach: The μFlux apparatus (pION Inc.) was used for permeability measurements. To avoid a pH change of BCB, a floating lid was newly developed for μFlux. The membrane filter was coated with a 10 % soybean lecithin-decane solution. The flux measurement was performed in an iso-pH condition (pH 6.5, BCB = 10 mM, buffer capacity (β)= 4.4 mM pH^-1). Phosphate buffer (PPB) with the same pH and β was used for comparison (PPB = 8 mM).

Key results: The floating lid suppressed the pH increase to less than 0.1 for 120 min. The effective permeability (P _e) values of lipophilic weakly acidic and basic drugs were lower in BCB than in PPB (ketoprofen, naproxen, and propranolol). On the other hand, the P _e values in BCB and PPB were similar for unionizable drugs (caffeine and antipyrine) and hydrophilic weakly basic drugs (metoprolol and procainamide).

Conclusion: Passive membrane permeation of lipophilic weakly acidic and basic drugs was slower in BCB than in PPB. This was suggested to be attributed to the slow neutralization rate of BCB, which affects the pH value adjacent to the membrane surface.