Biopharmaceutics & Drug Disposition最新文献

Rheumatoid arthritis is an auto-immune disease, commonly treated with celecoxib (Cyclooxygenase-2 inhibitor), which comes with serious cardiovascular threats. Astaxanthin is a natural carotenoid, possessing extraordinary anti-inflammatory and anti-platelet aggregation qualities. The aim of this study was to investigate the superlative effects of astaxanthin-hydrogel to inhibiting the cyclooxygenase-2 in comparison to celecoxib and its cardiac side-effects, specifically platelet aggregation. Induction of rheumatoid arthritis was accomplished by type-II-collagen/Complete Freund's adjuvant followed by a booster dose of Incomplete Freund's adjuvant and confirmed by arthritic score calculation, CRP and ACCPA tests. Astaxanthin-hydrogel was subcutaneously injected into the neck and back of arthritic Wistar rats in comparison to oral-celecoxib. Cyclooxygenase-2 inhibitory activity was observed by rat ELISA kit and platelet aggregation was monitored by optical chrono-log aggregometer. Results were compared by statistical analysis, executed through IBMM SPSS. The anti-inflammatory activity of 20 mg/week astaxanthin-hydrogel to inhibiting the cyclooxygenase-2 for 6 weeks in arthritic wistar rats was found more effective in comparison to 20 mg/day celecoxib. Continued use of 40 mg/day celecoxib for 8 weeks has been seen involved with platelet aggregation, whereas the regimen consisting of 20 mg/week astaxanthin-hydrogel administered with 20 mg/d celecoxib for 8 weeks was observed with no platelet aggregation. Celecoxib monotherapy was found associated with a little risk of platelet aggregation, whereas along with astaxanthin-hydrogel, no platelet aggregation was found. Notably, astaxanthin-hydrogel was significant to suppress the cyclooxygenase-2 in comparison to celecoxib.

Ampicillin (AMP) is an organic anion drug widely used in clinical setting as a β-lactam antibiotic. However, the specific transporter involved in mediating AMP transport remains unidentified. Thus, we investigated whether organic anion transporters1/3 (OAT1/3) mediate the renal transport of AMP in this study. Both rOAT1/OAT3 (Slc22a6/Slc22a8) double-knockout and wild-type (WT) rats were administered AMP via intraperitoneal injection simultaneously. Following the knockout, a significant increase in AMP plasma concentration and the area under the plasma concentration-time curve (AUC) was observed, accompanied by a marked reduction in cumulative urinary excretion. OAT1/3-overexpressing cell uptake experiments demonstrated that AMP is a substrate of OAT3, with a Michaelis-Menten constant (K_m) of 138.6 μM and a maximum transport velocity (V_max) of 80.43 pmol/mg protein/min. In conclusion, AMP was identified as a substrate of OAT3, rather than OAT1.

This study explored the advantages of two innovative concepts: AS and VBC. AS is a pharmacokinetic parameter that measures absorption rates, whereas VBC analyzes clinical endpoints as vectors, breaking them into independent components. Together, these methods aim to improve the accuracy and efficiency of bioequivalence (BE) studies. The performance of AS and VBC was assessed using 14 actual datasets. The study applied both standard statistical methods required by regulatory authorities and advanced techniques, including machine learning and artificial neural networks. The findings showed that combining AS and VBC accurately measures absorption rates while reducing variability. This approach enhances statistical power, addresses multiplicity issues, and supports smaller sample sizes. These improvements simplify BE studies, lower costs, and shorten completion times. The joint use of AS and VBC provides a precise and efficient method for defining absorption rates in BE studies. These methods improve study outcomes while reducing the resources and time required, making them valuable tools for modern BE analysis.

TPD354 is a novel Proteolysis Targeting Chimera (PROTAC) drug candidate that targets the degradation of cellular mesenchymal-epithelial transforming factor (c-Met) kinase. It showed significant therapeutic efficacy in vivo gastric cancer models. We have developed a robust and sensitive analytical method for evaluating the pharmacokinetic properties of TPD354, using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) to quantify drug concentrations in diverse biological matrices. The method was validated and applied to pharmacokinetic studies of the compound. The method exhibited excellent specificity in the linear range of 6.995-6995.000 ng/mL. Moreover, the method met or exceeded established criteria for precision, accuracy, recovery, and matrix effects, ensuring its suitability for in vivo analysis. The method was applied to the study of drug pharmacokinetics in rats, stability in different types of liver microsomes, and protein binding in plasma of different species. Our studies have demonstrated that TPD354 exhibits metabolic stability in liver microsomes and is characterized by high plasma protein binding, with a half-life of approximately 16 h in rats. These findings suggest that TPD354 is a promising PROTAC drug candidate, with strong potential for the treatment of c-Met targeted cancer.

Neurodegenerative diseases are progressive disorders that damage and eventually kill neurons in the central nervous system (CNS). In recent years, various research has been done on reliable and effective treatment methods for the most common neurodegenerative diseases such as Parkinson's, Alzheimer, and Migraine diseases. Different neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic, Lewy body disease can be treated by curcumin, which is a strong antioxidant polyphenol with neuroprotective and anti-amyloid properties. However, Blood-brain barrier (BBB) and blood cerebrospinal fluid barrier restricts the permeation of curcumin to the brain leads poor distribution of the drug in brain tissue. The intranasal pathway holds promise for enhancing the treatment of CNS disorders since it bypasses the BBB and increases the brain bioavailability of drug. As nanotechnology continues to improve, research on the delivery of drug through intranasal route has grown significantly in last 10 years. Several nanocarriers have been developed such as nano-emulsions, microspheres, dendrimers, liposomes, carbon-based nanoformulation, and nanoparticles to deliver curcumin to the brain via intranasal route for the treatment of neurodegenerative diseases. This study provided a thorough analysis of several curcumin nano-formulations used in intranasal pathway as a novel treatment for neurodegenerative diseases.

This study aimed to develop a CBD-loaded liposomal formulation (LIP/CBD) to improve its physicochemical properties and oral bioavailability (BA). LIP/CBD was prepared by the conventional solvent injection method. The physicochemical and pharmacokinetic properties of CBD were evaluated to clarify the possible improvement in the biopharmaceutical properties of CBD by the application of a liposomal system. For comparison, a cyclodextrin-based CBD formulation (CD/CBD) was prepared as a conventional solubilization system. Uniform spherical liposomes of LIP/CBD were observed by transmission electron microscopy, and the mean particle size was calculated to be approximately 120 nm with a polydispersity index of 0.13 and a zeta potential of -68 mV. The amount of CBD dissolved from crystalline CBD was very low under simulated intestinal pH condition (pH 6.8) due to its poor solubility and dispersibility. In contrast, LIP/CBD significantly enhanced the dissolution of CBD, as evidenced by 8-fold higher dissolution amount than that of crystalline CBD. Oral absorption of CBD from crystalline CBD was very poor owing to its low water solubility and severe first-pass metabolism. Orally administered LIP/CBD and CD/CBD exhibited significant improvements of oral absorption with 22- and 5.3-fold higher systemic exposure, respectively. The T_max of LIP/CBD was longer than that of CD/CBD, possibly due to the contribution of lymphatic absorption enhanced by lipidic components. The application of a liposomal system to CBD could be a viable option to enhance the physicochemical properties and oral BA of CBD.

The progress of drug designing, drug delivery systems (DDS), and disease diagnostic systems has significantly advanced pharmaceutical development, as evidenced by the FDA-approved nanomedicines with enhanced selectivity, controlled release, and synergistic therapeutic effects. However, the design and large-scale development of nanomaterial-based DDS remain challenging due to difficulties in managing and analyzing complex experimental data. The integration of data-driven techniques, high-throughput experimental networks and protocols, automation, artificial intelligence (AI), and machine learning (ML)-a framework known as the fourth paradigm of scientific research that offers a promising solution. This review article highlights milestones in applying these technologies to biomarker-based diagnosis and DDS, including nanomaterial design, and explores their potential to accelerate drug development and clinical translation. It also outlines the future prospects or directions for leveraging these approaches to create highly efficient, customizable nanomedicines and smart materials with defined physicochemical properties, aiming to benefit researchers in materials science, nanotechnology, and biomedical DDS development.

Vatiquinone, a 15-lipoxygenase (LO) inhibitor, is an orally bioavailable small molecule being developed for the treatment of Friedreich's ataxia, a disorder characterized by high levels of oxidative stress and dysregulation of energy metabolism. This investigation discusses the results of the food effect and three times a day (TID) dosing schedule studies data. The food effect study showed that absorption is significantly enhanced when vatiquinone was administered with fatty meals, either solid or liquid. Mean vatiquinone area under the concentration-time curve (AUC) values were 22-fold and 3-fold higher in subjects who consumed fatty meals and liquid meals, respectively, compared with subjects who fasted. With fatty meals, the intersubject variabilities appeared lower for AUC. The TID dosing study showed that the typical individual pharmacokinetic concentration profile exhibited 3 peaks on both Day 1 and after multiple dosing on Day 6. Vatiquinone exposures, AUC, and maximum concentration (C_max) appeared to increase from 200 to 400 mg in a dose-proportional manner with moderate variabilities, ranging from approximately 35% to 65%. The mean Day 6 accumulation ratio (AR_AUC) suggested an accumulation ratio of 1.61 and 1.73 for 200 and 400 mg, respectively. The results of both studies support the recommendation of administering vatiquinone TID with fatty meals taken on a convenient dosing regimen.

The pharmacokinetic (PK) profiles and parameters of betamethasone (BET) in seven species were collected and reviewed from the literature along with in-house rat data. The apparent clearance (CL/F) of BET was first evaluated using traditional allometric scaling methods, indicating that CL/F reasonably correlates with body weight (BW) with a power coefficient of 1.0 and R² = 0.93. A minimal physiological-based pharmacokinetic (mPBPK) model containing blood, two lumped tissue compartments, perfusion rate limited distribution, first-order absorption or prodrug conversion when needed, and utilizing the physiological and anatomical sizes of each of five species was implemented. The BET PK profiles were reasonably captured by the mPBPK model in the joint fitting analysis with a conserved partition coefficient (K_p = 0.99) and species-specific CL values. An allometric two-compartment model was also utilized and compared. Overall, the distribution properties of BET were reasonably conserved across species, but species-specific absorption rates and clearances provided best joint fitting of PK data across most species.

Tobacco is a major cause of chronic diseases such as lung cancer, cardiovascular disease, and chronic obstructive pulmonary disease worldwide. Nicotine, the primary psychoactive component in tobacco, is highly addictive and while not the primary driver of such tobacco-related diseases, poses various health risks, particularly those affecting the cardiovascular and pulmonary systems. Although nicotine-based therapies, such as nicotine replacement products, are widely utilized in smoking cessation efforts today, the impact of newer, tobacco delivery systems such as electronic nicotine delivery systems, or ENDS, remains uncertain and warrants continued evaluation. This study aims to develop and validate a physiologically based pharmacokinetic (PBPK) simulation model for nicotine using clinical pharmacokinetic data. The PBPK simulation model for nicotine was developed by incorporating drug-specific and system-specific parameters and by considering the systemic absorption, distribution, metabolism, and excretion of nicotine as well as its overall pharmacokinetic behavior on GastroPlus version 9.9. Validation of the developed PBPK model was performed by comparing predicted and observed plasma concentration-time profiles and pharmacokinetic parameters from clinical studies across multiple routes of administration including intravenous infusion, bolus, and pulmonary inhalation. The resulting model accurately captured plasma nicotine concentrations, with predicted pharmacokinetic parameters (C_max, T_max and AUCs) falling within acceptable ranges of observed values and computational average fold error values. The current model provides a practical tool to translate systemic nicotine exposure across delivery systems, support dose optimization against predefined target exposure, and quantify safety margins, thereby informing safer product design and evidence-based decisions in public-health regulatory science.