Drug Metabolism and Bioanalysis Letters - Online First
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A Physiologically-Based Pharmacokinetic Model to Characterize Dasotraline Pharmacokinetics and CYP-mediated Drug-Drug Interactions
Available online: 27 June 2025More LessIntroductionDasotraline 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 fm: 0.63) and, to a lesser extent, by CYP2D6 (fm: 0.12), CYP2C19 (fm: 0.11), and CYP3A4/5 (fm: 0.14). Dasotraline is not a CYP inducer but is an inhibitor of CYP2B6, CYP2C19, CYP2D6, and CYP3A4/5.
MethodsA dasotraline PBPK model was established by a middle-out approach based on in vitro and clinical results. Simulations were performed to evaluate CYP-mediated drug-drug 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.
ResultsThe 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.
DiscussionA PBPK model was developed via the middle-out approach to predict CYP-mediated 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.
ConclusionThe 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.
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Advancing Pediatric Drug Safety: The Potential of Physiologically Based Pharmacokinetic Modeling
Available online: 11 June 2025More LessPhysiologically 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.
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Navigating the Medicinal Benefits of Cubosome in Medicated Cosmetics for Potent Dermal Drug Delivery
Authors: Sumedha Saxena, Amol Kumar and Rashmi Saxena PalAvailable online: 19 May 2025More LessCubosomes, 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 cubosome-based 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.
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`3-Hydroxy-6H,7H-chromeno [3,4-c]chromene-6,7-dione as a Substrate for Studying Glucuronidation, Sulfonation and Lactone Hydrolysis
Available online: 25 April 2025More LessIntroduction/ObjectiveGlucuronidation and sulfonation enzymes conjugate compounds containing a hydroxyl group, while paraoxonase enzymes hydrolyze lactone-containing compounds. 3-Hydroxy-6H,7H-chromeno [3,4-c]chromene-6,7-dione (3-hydroxy-V-coumarin) contains both a hydroxyl substituent and two lactone substructures and is strongly fluorescent. This study evaluates glucuronidation, sulfonation and hydrolysis of 3-hydroxy-V-coumarin reactions, which abolish its fluorescence.
MethodsGlucuronide, sulfate, and hydrolyzed product formation were confirmed using accurate LC-MS. Fluorescence-based multi-well plate assays were established to determine rates of glucuronidation, sulfonation and hydrolysis of 3-hydroxy-V-coumarin.
ResultsA decrease in fluorescence correlated with the formation of conjugation or hydrolyzed metabolites of the reactions was observed. 3-Hydroxy-V-coumarin was glucuronidated by human UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2A1, 2B4 and 2B7 and by dog UGT1A1, 1A2 and 1A11, and sulfonated by human SULT1A1, 1A2 and 1E1. The results indicated that paraoxonase 2 hydrolyzed lactone of 3-hydroxy-V-coumarin. 3-Hydroxy-V-coumarin interacted via a hydrogen bond with serine 221 and via hydrophobic interaction with phenyls 71 and 291 of paraoxonase 2. The hydrolysis rate of 3-hydroxy-V-coumarin was determined in ten rat tissues. In human liver cytosol, the hydrolysis was slower than in rat, mouse, dog, pig, rabbit, and sheep liver cytosol.
Conclusion3-hydroxy-V-coumarin is a new model substrate for studying glucuronidation, sulfonation and lactone hydrolysis reactions
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Development and Validation of HPLC Method for Metformin and Canagliflozin in Bulk and Pharmaceutical Dosage Form Using the QbD Approach
Authors: Ansari Sajjad Husain Mumtaz Ahmad and Sunita S. DeoreAvailable online: 23 April 2025More LessIntroductionA 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.
MethodsThe 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.
ResultsThe technique developed for the analysis of MET and CAN exhibited an R2 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.
ConclusionThe 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.
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Navigating Drug Dynamics: Unleashing On-Chip Pharmacokinetics and Pharmacodynamics
Available online: 07 March 2025More LessAccurate 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.
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A Review on Pharmaceutical and Bio-Allied Applications of Infrared Spectroscopy
Authors: Muskan1, Bhawna Chopra, Sakshi Bhardwaj and Ashwani K. DhingraAvailable online: 26 February 2025More LessInfrared 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.
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