Biopharmaceutics & Drug Disposition最新文献

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.

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.

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.

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.

Methotrexate is an antifolate agent used for the treatment of various malignancies and is mainly secreted via human organic anion transporter 3 (hOAT3) in the proximal tubular cells. Coadministration of the xanthine oxidase inhibitor, febuxostat, in patients receiving methotrexate has been reported to be associated with an elevated risk of hematological toxicity and increased plasma methotrexate levels. Because febuxostat has an inhibitory effect against hOAT3, it may inhibit renal elimination of methotrexate via hOAT3. However, the drug interaction between methotrexate and febuxostat via hOAT3 remains to be clarified. In the present study, we investigated the effect of febuxostat on pharmacokinetics of methotrexate in rats and drug interaction between methotrexate and febuxostat using hOAT3-expressing cultured cells. In the pharmacokinetics study using rats, concomitant administration of febuxostat significantly increased plasma concentration of methotrexate and prolonged its half-life. In vitro studies showed that febuxostat inhibited hOAT3-mediated transport of methotrexate in a concentration-dependent manner. Dixon plot indicated that inhibitory constant value of febuxostat against methotrexate transport via hOAT3 was 0.63 ± 0.01 μM. Moreover, the inhibitory effect of febuxostat was of noncompetitive type. Taken together, these results suggest that concomitant administration of febuxostat delayed elimination of methotrexate, at least in part, by noncompetitive inhibition of hOAT3-mediated methotrexate transport at clinical concentrations. The findings of this study provide novel information on drug interactions associated with febuxostat.

This study investigated the effects of α-mangostin (α-MG) on the pharmacokinetics of tofacitinib in vitro and in vivo, aiming to recommend its appropriate application in clinical practice. To investigate the values of IC₅₀ and inhibition of α-MG in vitro, rat liver microsomes were incubated with tofacitinib. In this study, Sprague–Dawley rats were randomly assigned to three groups: a control group, a single-dose group (50 mg/kg of α-MG), and a multiple-dose group (50 mg/(kg/d) of α-MG for 7 days). Tofacitinib (10 mg/kg) was administered 30 min after the intervention of α-MG to each group. The plasma was collected from the caudal vein at different time points and in heparinized tubes. Tofacitinib metabolites in the plasma were determined by UPLC-MS/MS. Further analyses were conducted utilizing Pymol molecular docking simulation to evaluate the effect of α-MG on tofacitinib. Our results showed that MG inhibited the metabolism of tofacitinib in vitro by exhibiting both competitive and noncompetitive inhibition. More importantly, we found that multiple-dose administration of α-MG significantly increased the AUC_(0–12h), AUC_(0–∞), and C_max, prolonged the t_1/2 and shortened the MRT_(0–12h) and MRT_(0–∞) of tofacitinib. At the same time, the CL_z/F was decreased, which was consistent with the results of in vitro experiments. Furthermore, we observed no significant difference between single-dose and multiple-dose groups. Intriguingly, α-MG and tofacitinib were close at the CYP3A4 spatial location. In summary, our investigation demonstrated that α-MG significantly impacts the metabolism of tofacitinib both in vitro and in vivo, suggesting potential herb–drug interactions (HDIs). The use of tofacitinib with herbs containing MG should be monitored clinically.