Drug metabolism and bioanalysis letters最新文献

Purpose: The study aimed to develop and optimize a sustained-release matrix tablet of diclofenac sodium (50 mg) using carboxymethylated chitosan (CMCS) as the matrix- forming polymer, in combination with hydroxypropyl methylcellulose (HPMC). The research investigated the impact of CMCS (50-200 mg) and HPMC (150-300 mg) composition on the critical quality attributes of the sustained-release matrix tablets.

Methods: A 2-factor mixture design investigated the impact of HPMC and CMCS proportions on critical quality attributes. Tablets (650 mg) were prepared by wet granulation and characterized for flow properties, hardness, and drug release kinetics. The in vitro drug release studies were carried out at 37 ± 0.5°C in a phosphate buffer of pH 6.8 using a USP type II dissolution apparatus operated at 50 rpm. The in vitro dissolution profile of the optimized formulation was compared with a marketed product, Reactin® SR, using ANOVA and model-independent methods (f1 and f2 values).

Results: Granule properties showed good flow characteristics with Carr's index (14.25- 18.36) and Hausner ratio (1.05-1.25). FTIR and DSC studies confirmed no drug-excipient interactions, with the drug's characteristic peaks maintained at 766 cm⁻¹, 1454 cm⁻¹, 1017 cm⁻¹, and 2915 cm⁻¹, and a melting endotherm at 54°C. The optimized formulation (F3) with 150 mg HPMC and 200 mg CMCS demonstrated 90.57% drug release in 8 hours following super case II transport (n = 1.11). The release kinetics best fitted the Korsmeyer- Peppas with the F0 model (R² = 0.9959). The response parameters hardness (4.2 ± 0.126 kg/cm²), t25 (115 ± 11.60 min), t50 (290 ± 21.42 min), and t90 (630 ± 31.51 min) were best fitted to the quartic model. The similarity factor (f2 = 67.63) and difference factor (f1 = 13.85) indicated the equivalency of the dissolution profile with that of the marketed formulation.

Conclusion: The study successfully developed a sustained-release matrix tablet of diclofenac sodium using CMCS as the primary matrix material. The optimized formulation demonstrated a dissolution profile comparable to the marketed product (>90% release in 8 hours), with f2 > 50 and f1 < 15, suggesting its potential as a generically equivalent alternative. Moreover, the findings indicate that CMCS is an effective carrier for sustainedrelease formulations and can potentially be applied to other drugs requiring controlled release.

Background: Microbial biotransformation of steroids is a valuable method for producing active pharmaceuticals or potentially active steroids, and fungi serve as powerful biocatalysts in this process. On the other hand, in silico analyses are preliminary yet influential studies for the evaluation of compounds in the drug development process.

Objective: This study aimed to examine the ability of Mucor hiemalis to biotransform hydrocortisone, predict the potential binding ability of the products to the 11β- hydroxysteroid dehydrogenase enzyme (as a target for the control of diabetes mellitus type 2), and assess the products' pharmacokinetic properties.

Methods: The incubation of M. hiemalis with hydrocortisone for nine days resulted in the production of a main product in the culture medium. The metabolite was subsequently isolated using chromatographic procedures and its identity was determined by spectroscopic analysis. Computational binding studies and pharmacokinetic profile prediction of the metabolite were conducted using AutoDock Vina and SwissADME, respectively.

Results: The biotransformation of hydrocortisone by M. hiemalis produced 11β,17α,20β,21-tetrahydroxypregn-4-en-3-one as the major metabolite. Molecular docking studies demonstrated that the metabolite can interact with functional residues located at the catalytic site of the enzyme in different ways. Furthermore, the results indicated a favorable pharmacokinetic profile of the produced metabolite.

Conclusion: The current study showed that M. hiemalis may be considered an effective tool for the biotransformation of steroids and the production of potentially bioactive compounds.

Background: Efinaconazole is a topical antifungal medication that is effective against fungal infections of the toenails. In addition, due to its application on the skin, minimal systemic absorption takes place on the epidermic layer, which leads to the availability of lower-level concentration in the bloodstream. Although several reported methods in the literature describe the quantification of Efinaconazole using conventional techniques like HPTLC and HPLC, these methods lack the necessary sensitivity and selectivity to be directly applied for quantification in biological samples.

Objective: Current research work aimed to develop a rapid, specific, selective, and sensitive method using plasma as one of the biological samples for quantification of Efinaconazole (EZ) in the presence of Fluconazole (FZ) as an internal standard by tandem mass spectrometry (LC-MS/MS).

Methods: Chromatographic separation was achieved with a Thermo Hypersil Gold (100 mm x 2.1 mm, 1.9 μm) UPLC column using a mobile phase composed of 20% formic acid-water (0.1%) and 80% methanol. Liquid-liquid extraction (LLE) was employed for sample preparation. Efinaconazole and the internal standard were detected using the heated electrospray ionization (HESI) technique in parallel reaction monitoring (PRM) mode.

Results: The developed method displayed a linearity range of 1 to 2000 pg/mL (0.001-2 ng/mL). Precision and accuracy for the lower limit of quantitation, low, mid, and high-quality control (QC) levels demonstrated a variance of less than 5% and an accuracy of 99 to 103%. Long-term stability was confirmed under various conditions, including storage in an auto-sampler, at room temperature, in a deep freezer, and after freeze-thaw cycles.

Conclusion: The validated LC-MS/MS method has exceptional sensitivity, specificity, selectivity, rapid analysis, minimal requirement of sample quantity, wide dynamic range of concentration, robustness, and reproducibility, making it an indispensable tool, especially in fields of in vitro Permeation Testing (IVPT), in vitro Release Testing (IVRT), Pharmacokinetic, Toxicology, Clinical studies, and in drug development program for the quantification of Efinaconazole.

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease which leads to pain and disability that may trigger anxiety and sleep disturbances. Naproxen and St. John's Wort concomitant administration in RA and anxiety raises the question of safety due to a potential drug interaction.

Materials and methods: Albino Wistar rats were treated with naproxen and St. John's Wort for 30 days. The study involved the evaluation of safety of naproxen when combined with St. John's Wort by estimation of biochemical markers such as SGOT, SGPT, TG's, Creatinine, BUN, the extent of gastromucosal damage and estimation of AUC, t1/2 and Clearance using blood serum analysis with HPLC after 30 days of treatment. Histopathological studies were also conducted to determine the tissue architecture.

Results: Elevated levels of hepatic markers SGOT, SGPT, TG, and gastro-mucosal damage with enhanced ulcer index were found in naproxen-St. John's Wort treated rats as compared to only naproxen treated rats. HPLC analysis displayed increased AUC and t1/2 of naproxen with decreased clearance in naproxen-St. John's Wort treated rats. Histopathological findings revealed tissue rupture and mucosal damage supporting the naproxen toxicity.

Conclusion: Consulting a healthcare professional before combining St. John's Wort with naproxen is essential to assess potential risks, manage drug interactions, and ensure safety. Personalized advice helps optimize treatment outcomes for both rheumatoid arthritis and mental health.

Introduction: One of the world's most serious health issues is arsenic toxicity. Prolonged consumption of Arsenic contaminated water causes cognitive damage in the developing and adult brain. The present research investigated how sodium arsenite-induced neurotoxicity in SD rats was affected by rolipram, a PDE4 inhibitor, and vinpocetine, a PDE1 inhibitor.

Methods: The arsenic concentration was determined, which indicates the accumulation of arsenic in blood. The low weight of the brain indicates the adverse effects on the brain, which was significantly improved by rolipram and vinpocetine. Biochemical markers (MDA, GSH, CAT, and SOD) and protein expression of CREB and P-CREB were studied in the hippocampal region of the brain.

Results: The reduced antioxidant activity and elevated levels of inflammation were significantly improved by rolipram and vinpocetine administration. Additionally, rolipram and vinpocetine significantly increased the CREB and P-CREB expression in the hippocampi of rat brains.

Conclusion: PDE4 and PDE1 inhibition in arsenic-induced neurotoxicity could be a novel approach and a new drug therapy for arsenic-induced neurotoxicity.

developing area of clinical interest is the potential interactions between drugs and herbal products. The potential risk of an interaction between green tea (Camellia sinensis) and alprazolam, a benzodiazepine that is commonly recommended for anxiety disorders, is discussed in this review. Numerous bioactive components included in green tea, such as caffeine and catechins, may alter the pharmacokinetics of alprazolam by altering its metabolism, excretion, or absorption. It has been shown that green tea affects the activity of cytochrome P450 enzymes, particularly CYP3A4, which is involved in alprazolam metabolism. Green tea may increase alprazolam plasma levels and increase the likelihood of adverse effects, such as drowsiness or motor incoordination due to CYP3A4 inhibition, which will be studied from the existing literature and pharmacological evidence. While definitive clinical trials are limited, the aim of the review is to emphasize the necessity for increased awareness among healthcare practitioners and patients regarding potential drug-herb interactions, especially in individuals utilizing anxiolytic drugs along with green tea consumption. Additional clinical investigations are necessary to formulate solid guidelines for the safe consumption of green tea by those using alprazolam.

Background: This study developed a UV spectrophotometric method for quantifying allopurinol and lycopene in both bulk and dosage forms, aiming for simplicity and practicality.

Materials and methods: The method was developed and validated using methanol and lycopene in phosphate buffer saline at various pH levels (7.4, 6.8, 1.2, 5.5). Validation parameters included linearity, accuracy, precision, limit of quantification (LOQ), and limit of detection (LOD) according to ICH standards.

Results: The method demonstrated high sensitivity and linearity over a concentration range of 4-20 μg/ml, adhering to Beer's law. The LOQ and LOD were 2-18 μg/ml and 2-6 μg/ml, respectively. Optimal absorbance wavelengths were 251 nm for lycopene and 471 nm for allopurinol. Calibration curves showed a high correlation coefficient (0.9994), indicating a strong linear relationship.

Conclusion: The developed UV spectrophotometric method is effective, interference-free, and suitable for routine quality control, providing reliable measurements for allopurinol and lycopene.

Background: Nicotine addiction remains a significant public health challenge, driving the need for effective treatment strategies. While various pharmacological approaches have been explored, targeting neurotransmitter and neuromodulator systems offers a promising avenue. These systems, particularly those involving dopamine, play a pivotal part in interceding the rewarding effects of nicotine and the development of dependence. Serotonin, a pivotal neuromodulator, exerts a profound influence on dopamine pathways. By interacting with these pathways, serotonin can significantly impact the substantiating effects of nicotine. Understanding the intricate interplay between serotonin and dopamine systems is pivotal for developing new remedial interventions that effectively address the intricacies of nicotine dependence.

Objective: The purpose of this research study was to examine the potential roles played by serotonin and its receptors in nicotine addiction by examining the involvement of serotonin modulators in the development of conditioned location preference in mice after exposure to nicotine.

Methods: Mice were subjected to conditioned place preference (CPP) training with nicotine. After induction of CPP, the extinction session was given for the disappearance of CPP. There were a total of five groups, each having six animals that participated in the experiments, including group 1 (controls; normal saline), group 2 (nicotine A; 0.25 mg/kg), group 3 (nicotine B; 0.5 mg/kg), group 4 (nicotine C; 0.75 mg/kg), and group 5 (standard drug; fluoxetine). All drugs were given through the subcutaneous route. The treatment of serotonin modulators, i.e., fluoxetine (100 mg/kg), a selective serotonin reuptake inhibitor (SSRI), was given before the priming dose of nicotine, and the effect of the serotonin modulator was observed.

Results: On day 17th, the CPP values were 390.16 s, 235.66 s, and 219.16 s, respectively, for nicotine A, nicotine B, and nicotine C in the black compartment groups; however, in the white compartment groups, the CPP values were 347.16 s, 588 s, and 549.66 s, respectively, for nicotine A, nicotine B, and nicotine C.

Conclusion: Using the conditioned place preference (CPP) paradigm, we administered both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Long-term fluoxetine users may benefit more from the drug than those who have only used it occasionally or in small doses, according to the study.

Aim: The current study focused on formulating ocular films embedded with levofloxacin for the treatment of conjunctivitis by employing the solvent-casting technique.

Methods: These films were formulated with gelatin, Aloe barbadensis leaves mucilage (ABLM), and HPMC K4M to enhance the therapeutic effectiveness of levofloxacin. Various evaluations were carried out to confirm the quality and stability of the films, including assessments of thickness, weight uniformity, uniformity in LFX, % loss of moisture, and permeation. In vitro drug release studies were conducted to simulate ocular environments and analyze the precise release of LFX.

Results: The films exhibited uniform thickness (0.15-0.19 mm) and weight (61.85-65.54 mg) with a consistent film area (0.502 cm²). LFX content ranged from 85.66% to 97.03%, with T-6 being the most uniform. Moisture loss was found to be 7.98-9.55%, and absorption (highest in T-6, i.e., 18.05%) increased with gelatin. LFX permeation peaked at 97.03% (T-6) in 24-h diffusion studies. T-8 demonstrated exceptional mucoadhesion (>10 h), and ANOVA confirmed the important influence of gelatin, ABLM, and HPMC K4M on LFX content (F-value: 129.91, p=0.0010).

Conclusion: The study concluded that combining ABLM with HPMC K4M enabled consistent, diffusion-controlled release of LFX, offering an effective and sustained formulation for treating conjunctivitis.

Introduction: This paper aimed to establish a method to help investigate the combination mechanism of traditional Chinese medicine from the metabolic perspective.

Background: Semen Strychni has been a frequently used herb in clinics for a long time. In traditional Chinese medical science, Semen Strychni always combinate with other herbs to modulate its nature of severe toxicity. However, the mechanism of the combination is still unclear. Previous research mostly focused on the components of the herbs. The metabolic processes of the main components of the Semen Strychni are also very important and have rarely been reported.

Objective: This study tended to develop a rapid and sensitive high-performance liquid chromatographic- tandem mass spectrometric (HPLC-MS/MS) method for the determination of two major metabolites of Semen Strychni in rat urine.

Methods: Chromatographic separation was carried out on a C18 column. Detection was performed by a selective reaction monitoring (SRM) mode via an electrospray ionization (ESI) source operating in the positive ionization mode. Analysis of analytes from rat plasma was carried out by protein precipitation using acetonitrile.

Results: The assay was validated in terms of specificity, precision, recovery, etc. The intra- and inter-day precision values were less than 13.1%. The recoveries at three levels were more than 69.1%. The method was then used to study the kinetic profiles of the metabolites of Semen Strychni in rat urine for the first time.

Conclusion: The results demonstrate that the established LC/MS method in this study is accurate and sensitive for the simultaneous determination of the two metabolites of Semen Strychni in rats' urine samples. This method could be a supplement to the plasma pharmacokinetics of Semen Strychni.