Drug metabolism and bioanalysis letters最新文献

Cubosomes, nanoscale liquid crystalline particles, represent a groundbreaking advancement in dermal drug delivery for medicated cosmetics. These innovative structures feature a three-dimensional cubic lattice formed through the self-assembly of lipid molecules, which possess both hydrophilic and hydrophobic domains. This unique composition allows cubosomes to form stable, water-dispersible nanoparticles, making them ideal carriers for active pharmaceutical ingredients. In medicated cosmetics, cubosomes offer the dual advantage of improving therapeutic outcomes and enhancing patient compliance while minimizing adverse effects. Their controlled release mechanisms significantly increase drug bioavailability at the target site, providing a more effective and localized treatment. Key factors influencing the efficiency of cubosomebased drug delivery systems include (i) the lipid composition, (ii) surface modifications to improve stability and interaction with the skin, (iii) the use of penetration enhancers to facilitate deeper skin absorption, and (iv) the size of the cubosomes, which impacts their ability to navigate the dermal layers. Ongoing research in this field focuses on optimizing cubosome formulations for specific medications and therapeutic applications. By refining these parameters, researchers aim to harness the full potential of cubosomes, paving the way for innovative and effective dermatological treatments in medicated cosmetics.

Objective: A unique liquid chromatography-tendon mass spectrometric technique for the determination of metformin and vildagliptin in K3EDTA human plasma was developed and verified as per the USFDA guidelines of bioanalysis.

Methods: The chromatographic separation was achieved using a Cosmosil CN (150 x 4.6 mm, 5 μm) column with an isocratic elution pattern using 10 mM ammonium formate (pH 5.0) and methanol in the ratio of 30:70 v/v as a mobile phase. A mass spectrometer coupled with an electrospray ionization (ESI) source operating in the positive ion was used for detection. Data were obtained in the multi-reaction monitoring (MRM) acquisition mode. Metformin D6 and vildagliptin D7 were used as internal standards, with the flow rate at 1.0 mL/min throughout the experiment. The drugs were extracted by solid phase extraction (SPE) packed with Phenomenex Strata-X. Extraction of the drug was achieved using methanol: 5 mM sodium lauryl sulphate solvent mixture in equal proportions.

Results: The retention time for MET and VLG were 3.2 and 3.8 minutes individually. The drugs were extracted by SPE with good recovery of 89.44% and 87.57% for metformin and ISTD and 92.26% and 89.58% for vildagliptin and ISTD, respectively. Sample elution was performed using solid phase extraction (SPE), and this technique produced very pure extracts with good recovery rates. A liner calibration curve was found in the range of 0.5-400 ng/mL for MET and 0.2-160 ng/mL for VLG with a correlation coefficient r2 > 0.99.

Conclusion: The aforementioned technique is reliable and effective for monitoring bioequivalence investigations in human participants.

Deoxyribonucleic acid (DNA) is the crucial molecule that stores and transmits genetic information in living organisms. DNA can incur damage from various sources, necessitating efficient DNA repair mechanisms to maintain genomic stability. Cells employ multiple repair pathways, including single-strand repair and double-strand break repair, each involving specific proteins and enzymes. PARPs play a fundamental role in the repair of DNA to detect damage to DNA and facilitate the repair process. PARPi are drugs that inhibit PARP activity, leading to DNA damage accumulation and cell death, particularly in cancer cells with impairments in DNA repair pathways, such as BRCA1/2 mutations. Additionally, PARPi is promising in treating cancer, offering a targeted therapeutic approach. Resistance to PARP inhibitors continues to be an issue in a major clinical challenge. Mechanisms of resistance include homologous recombination repair restoration, increased drug efflux, and mutations in the PARP1 enzyme. Moreover, to overcome this resistance, researchers are investigating combination therapies, targeted therapies that inhibit complementary DNA repair pathways, and novel agents that can counteract resistance mechanisms. Future perspectives focus on enhancing our understanding of resistance mechanisms, developing more effective and selective PARP inhibitors, and identifying predictive biomarkers for therapy response. These advancements aim to improve the efficacy and durability of PARP inhibitor-based treatments, ultimately leading to better outcomes for cancer patients. This review article focuses on the reasons for the evolution of PARP inhibitors, the mechanisms behind resistance, and new strategies to overcome this resistance.

Recently, polymeric systems have emerged as the most practical and adaptable delivery method for targeted cancer therapy. Surface functionalization of polymers is one of the delivery methods of targeted drugs. For instance, to increase the selectivity and affinity of polymers for cancer cells, targeting moieties are covalently bonded on their surface. The surface decoration of polymers with a particular tumor-homing ligand, such as an antibody, an antibody fragment, a peptide, an aptamer, a polysaccharide, a saccharide, folic acid, etc. may also increase drug retention and accumulation in the tumor vasculature as well as promote efficient internalization by target tumor cells. This study discusses the recent development of polymeric systems coupled with particular targeting ligands for cancer cell targeting. Additionally, attention is given to the various polymers utilized in cancer therapy and how their surface decoration contributes to cancer cell targeting. We conclude that the surface- modified polymeric system in cancer cell targeting has emerged as a promising platform for safe and effective cancer therapy with the potential to maximize therapeutic efficacy while minimizing systemic side effects.

Infrared spectroscopy has emerged as a powerful analytical technique with diverse applications in the pharmaceutical and bio-allied domains. This article provides an in-depth exploration of the method's utility in pharmaceutical applications, including identification, moisture content determination, and assay of pharmaceutical compounds. Additionally, it delves into the extensive role of infrared spectroscopy in bio-allied research, encompassing the investigation of structural arrangements, interactions, mobility, and dynamics of biomolecules. In the realm of pharmaceuticals, infrared spectroscopy stands as a reliable tool for the identification of compounds, ensuring the authenticity and quality control of drug formulations. The capacity to measure moisture content is crucial in ensuring the stability and efficacy of medicinal goods. Furthermore, the assay of pharmaceutical compounds by infrared spectroscopy offers a rapid and precise means of quantifying active ingredients, supporting the development and production of pharmaceutical formulations. In the bio-allied field, the versatility of infrared spectroscopy becomes evident in its contribution to understanding the intricate details of biomolecular structures and interactions. The method plays a pivotal role in investigating the structural arrangements of macromolecules, shedding light on the complexities of biological systems. Additionally, infrared spectroscopy facilitates the assessment of body fluids, enabling non-invasive diagnostics and monitoring of health conditions. The article also explores the application of infrared spectroscopy in the analysis of blood, providing valuable insights into hematological parameters and contributing to diagnostic methodologies. The method's wide-ranging influence on healthcare and forensic sciences is demonstrated by its promise in cancer detection, forensic investigations, and hematological illness monitoring.

Physiologically Based Pharmacokinetic (PBPK) modeling represents an advanced computational model that bridges the gap between theoretical pharmacology and clinical practice. These advanced mathematical frameworks integrate complex physiological parameters with absorption, distribution, metabolism, and excretion (ADME) processes to create dynamic simulations of drug behavior in biological systems. By providing mechanistic insights into drug disposition and interactions, PBPK models have become indispensable tools in modern drug development and clinical therapeutics. The evolution of PBPK modeling has particularly revolutionized pediatric pharmacology, where traditional dosing paradigms often fall short due to the unique physiological characteristics of developing organisms. These models excel in their ability to predict pharmacokinetic profiles across diverse age groups, offering crucial insights into the fundamental differences between adult and pediatric drug handling. Their capability to anticipate drug-drug interactions (DDIs) has proven especially valuable in pediatric settings, where complex medication regimens are increasingly common. The growing adoption of PBPK modeling by pharmaceutical companies, regulatory agencies, and clinical institutions underscores its pivotal role in contemporary drug development. These models demonstrate remarkable effectiveness in translating adult pharmacokinetic data to pediatric populations, integrating multiple evidence streams to elucidate age-specific differences in drug disposition. This translational capacity has become particularly crucial in optimizing pediatric drug development strategies and enhancing therapeutic decision-making. This article presents a comprehensive analysis of PBPK modeling, examining its foundational principles and recent advances in adult-to-pediatric pharmacokinetic translation. Special attention is devoted to the unique challenges and emerging solutions in pediatric PBPK (P-PBPK) modeling, particularly in the context of DDIs. Through detailed exploration of these aspects, we illuminate how PBPK modeling continues to advance our understanding of drug behavior in pediatric patients, ultimately contributing to more precise and safer therapeutic interventions for this vulnerable population.

Introduction: A simple, precise, robust, and accurate high-performance liquid chromatography (HPLC) technique has been devised and validated for the simultaneous quantification of canagliflozin (CAN) and metformin (MET) in the dose form of combination tablets.

Methods: The significance and interaction effects of independent variables on the response factors were evaluated using 3² factorial design. Analysis of variance (ANOVA) and plots displayed the final chromatographic conditions of the procedure. Methanol: water separation was carried out using a C18 column (4.6 mm × 250 mm; 5 μm). Ultraviolet (UV) detection at 255 nm was found to have good sensitivity. Following the development of the method, its accuracy, precision, linearity, and robustness with the active substances were examined.

Results: The technique developed for the analysis of MET and CAN exhibited an R²2 value of 0.999. The method's relative standard deviation (%RSD) for accuracy and precision was discovered to be less than 2%. The recovery research, which was conducted at 50, 100, and 150% levels, was used to determine the accuracy of the procedure. The precision of the approach was examined using repeatability, intraday, and interday analysis; a low percentage of RSD suggested a high level of precision for the suggested method.

Conclusion: The regular analysis of MET and CAN in their combined dose form can be effectively conducted using the suggested methodology. The results have shown the recommended method as suitable for both the precise and accurate formulation of MET and CAN and their bulk determination.

Introduction: Dasotraline is an investigational inhibitor of dopamine and norepinephrine reuptake transporters that has completed pivotal studies in Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED). Preclinical studies show dasotraline is well absorbed, well distributed, and highly metabolized in animal models, though absorption is prolonged with slow overall elimination in humans. Dasotraline is a substrate of multiple Cytochrome P450s (CYP). The metabolism of dasotraline is largely determined by CYP2B6 (fraction of metabolism f_m: 0.63) and, to a lesser extent, by CYP2D6 (f_m: 0.12), CYP2C19 (f_m: 0.11), and CYP3A4/5 (f_m: 0.14). Dasotraline is not a CYP inducer but is an inhibitor of CYP2B6, CYP2C19, CYP2D6, and CYP3A4/5.

Methods: A dasotraline PBPK model was established by a middle-out approach based on in vitro and clinical results. Simulations were performed to evaluate CYP-mediated drugdrug interactions (DDI) with dasotraline as a victim and perpetrator, the impact of polymorphic CYP2B6 on dasotraline PK, as well as the role CYP2B6 autoinhibition on dasotraline accumulation at steady state.

Results: The PBPK model well described clinically observed PK not only after a single dose, but also predicted substantial accumulation of dasotraline due to auto-inhibition of CYP2B6-mediated clearance. In addition, the simulated CYP2B6-mediated DDI precisely depicted the clinically observed DDI. Although hepatic elimination of dasotraline is primarily mediated by CYP2B6, simulations suggest that the impact of CYP2B6 polymorphism on pharmacokinetics is minimal, likely due to compensatory auto-inhibition of the enzyme. As a result, dose adjustment based on CYP2B6 phenotype is likely unnecessary.

Discussion: A PBPK model was developed via the middle-out approach to predict CYPmediated DDI with dasotraline as either a victim or a perpetrator and the impact of polymorphic CYP2B6 on dasotraline PK. The PBPK model was developed assuming the hepatic metabolism of dasotraline is only determined by CYP enzymes based on the in vitro studies. Although the minor contribution of non-CYP enzymes may not be ruled out, the simulations on CYP mediated DDI with dasotraline as the victim will unlikely be significantly different.

Conclusion: The PBPK model developed via the middle-out approach provides a quantitative tool to predict CYP-mediated DDI with dasotraline as either a victim or a perpetrator and the impact of polymorphic CYP2B6 on dasotraline PK. This model may aid in optimizing dosing strategies to minimize the risks associated with CYP-mediated interactions and significant accumulation following repeated dosing.

Accurate prediction of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) is a key component in using the drug as a therapeutic. Traditionally many in vitro and in vivo techniques are used for ADMET profiling in pre-clinical studies. Due to the absence of all cellular parameters and inter-species variability, the obtained pre-clinical study results were not reproducible in clinical trials. As a result, both industry and academic researchers find drug discovery and development to be a daunting task due to several constraints. A reliable and simple approach is, therefore, needed for in vitro PK-PD studies. The new ray of hope in this field is the Organ- on-a-Chip (OoC) technique. On one side, it is an in vitro technique, and on another side, it can reliably produce reliable PK/PD results. In this review, we primarily focused on the application and scope of OoC technology in the field of PK/PD studies. We believe this review will be helpful for future researchers in this domain.