In a previous study, retrospective predictions of human serum concentration-time profiles for three therapeutic monoclonal antibodies (mAbs) with linear pharmacokinetics were performed using allometric scaling in common marmosets and achieved favorable predictability. To generalize this method, in the present study, golimumab and ustekinumab, which exhibit linear pharmacokinetics, were repeatedly administered to marmosets. Additionally, the immunogenicity of these mAbs in common marmosets was evaluated. Golimumab and ustekinumab were administered in four repeated doses. Following the initial administration, the scaling exponents of the two mAbs were calculated, and the average scaling exponents of the five mAbs were used for the predictions. Furthermore, serum anti-ustekinumab and anti-golimumab antibodies were evaluated following the repeated-dose administration. Human serum concentration-time curves of golimumab and ustekinumab were predicted using the average scaling exponents of the five mAbs. Although the predictability of the golimumab elimination rate was slightly inferior, ustekinumab showed excellent prediction performance. Low levels of anti-ustekinumab antibodies were detected in the serum when the serum ustekinumab levels were considered to have completely diminished. Furthermore, serum anti-golimumab antibodies were negligible during the experimental period. We identified provisional optimal scaling exponents for predicting human PK and found minimal anti-drug antibody formation. As the cost of acquiring and maintaining cynomolgus monkeys is increasing, pharmacokinetic data of marmosets is expected to encourage the potential use of these small non-human primates as an alternative model.
Glomerular filtration rate (GFR) maturation is critical for drug dosing in neonates and children. Current equations face dual limitations: they are primarily derived from Caucasian populations and fail to account for the fundamental physiological differences between neonates and children. This study aimed to develop Chinese-specific GFR equations and to characterize how the key predictors of GFR differ between these two developmental stages. Creatinine clearance as measured GFR (mGFR) in 58 hospitalized neonates (gestational age range, 30.3-41.0 weeks, postnatal age range, 0 to 26 days, mGFR = 3.08 ± 1.86 mL/min) without renal impairment were enrolled. Moreover, a published database of Chinese children (N = 87, age range, 1 to 18 years, mGFR = 97.0 ± 31.9 mL/min/1.73 m2) was applied. Demographic and renal function markers were included to develop equations using the stepwise regression method in allometric form. The GFR prediction equation of serum cystatin C, blood urea nitrogen and postmenstrual age of Chinese neonates was established. In children, GFR is associated with cystatin C, creatinine, weight and age. In an internal comparison with 16 published equations, our newly developed models showed favorable performance within our cohorts, with correlation (R2 of 0.617 and 0.578) and accuracy (P20 of 46.6% and 70.1%, P50 of 93.1% and 100%), respectively. The equations would provide scientific basis for aiding diagnosis of renal function of Chinese neonates and children, and supporting better precision medicine of drugs mainly excreted by kidney.
Echinacea is a widely used herbal supplement and is frequently co-administered with antiviral drugs, raising concerns regarding potential herb-drug interactions. This study evaluated the effect of repeated Echinacea administration on the pharmacokinetics of favipiravir and atazanavir in rats. Male Sprague Dawley rats were administered Echinacea (250 mg/kg) or vehicle once daily for 10 days, followed by a single oral dose of favipiravir (70 mg/kg) or atazanavir (35 mg/kg). Plasma drug concentrations were quantified using validated LC-MS/MS methods, and pharmacokinetic parameters were determined by noncompartmental analysis. Echinacea co-administration did not significantly alter favipiravir exposure (Cmax: 39,677 ± 5385 vs. 36,364 ± 5379 ng/mL; AUC0-t: 144,457 ± 17,267 vs. 104,840 ± 27,001 ng h/mL) or atazanavir exposure (Cmax: 3274 ± 256 vs. 4004 ± 629 ng/mL; AUC0-t: 8962 ± 1667 vs. 10,645 ± 2949 ng h/mL). No relevant changes were observed in clearance, half-life, or mean residence time for either drug. These findings indicate that repeated Echinacea administration does not result in a pharmacokinetically relevant interaction with favipiravir or atazanavir under the investigated conditions.
This study is the first attempt to develop a novel slowly self-emulsifying drug delivery system (SL-SEDDS) of sesamin (SES) for improved biopharmaceutical properties. Firstly, SES-loaded self-emulsifying drug delivery system (SEDDS/SES) comprising krill oil, medium-chain triglyceride, Tween 80, and propylene glycol with 1.5 w/w% SES loading was prepared and optimized using a pseudo-ternary phase diagram. Then, SES-loaded SL-SEDDS (SL-SEDDS/SES) was produced by mixing the optimized SEDDS/SES with varying Geleol (solid lipid) contents. The resulting formulations were evaluated in terms of their physicochemical properties and pharmacokinetics. The self-emulsifying potency of SL-SEDDS/SES remained largely unaffected by the presence of Geleol. The dissolution behavior of SES in SL-SEDDS/SES improved relative to that of crystalline SES, with sustained release that was dependent on Geleol content. Notably, SL-SEDDS/SES containing 20 w/w% Geleol content (SL-SEDDS/SES-20) performed favorable sustained release with 65% dissolved SES at 6 h. After oral administration of SES samples (20 mg-SES/kg) in rats, SL-SEDDS/SES-20 showed 7.9-fold higher area under the curve of plasma concentration-time profile than that of crystalline SES. Additionally, it reduced the peak systemic exposure observed with SEDDS/SES, with a 22% lower Cmax and a prolonged mean residence time (MRT) of 5.3 h. These findings suggest that SL-SEDDS is a promising dosage form for enhancing the biopharmaceutical properties of SES and potentially other lipophilic nutraceuticals.
Voriconazole (VCZ) is a broad-spectrum antifungal agent widely used for treating fungal infections caused by Candida, Aspergillus, and Fusarium species, which are commonly associated with fungal keratitis (FK). Topical ophthalmic ointments offer several advantages over conventional eye drops, including prolonged retention on the ocular surface, sustained drug release, and improved bioavailability. In this study, we formulated and optimized a VCZ-loaded ophthalmic ointment intended for effective management of FK. The ointments were prepared using emulsifying wax and varying proportions of liquid paraffins through the fusion method. Among all the formulations, batch F4 demonstrated optimal properties, including a stable, opaque white appearance with drug content of 103.7 ± 2.4%. Microscopic examination showed no drug crystallization, and differential scanning calorimetry (DSC) confirmed the absence of drug-excipient interactions. The in vitro release profile of F4 showed 70% drug release over 24 h, fitting the Higuchi kinetic model, indicative of a sustained release pattern. Ex vivo transcorneal studies revealed that 13.22 ± 0.81% of the drug permeated across the cornea, while 2.51 ± 0.03% remained entrapped in the corneal tissue after 24 h. Ocular irritation studies demonstrated the formulation was non-irritant and safe for ophthalmic use. Furthermore, in vivo pharmacokinetic evaluation in rabbits showed significantly higher corneal drug concentrations for F4 (Cmax: 400.76 ± 70.13 μg/mL) compared to a marketed formulation (Cmax: 32.60 ± 26.64 μg/mL), indicating approximately 12-fold enhanced retention. These findings suggest that the optimized ointment is a promising option for effective and prolonged ocular delivery of VCZ in the treatment of FK.
Voriconazole, a broad-spectrum triazole antifungal, is widely prescribed for fungal keratitis (FK) caused by Candida, Aspergillus, and Fusarium species. Conventional ophthalmic solutions are limited by rapid clearance and low bioavailability. This study describes the development of a voriconazole-loaded ophthalmic emulsion to improve ocular residence and drug disposition. Emulsions were prepared with soybean oil and Tween 80 via high-shear homogenization, with batch VE-3 exhibiting favorable properties, including nanosized globules (95.8 ± 50.2 nm, PDI 0.197), pH 6.94 ± 0.14, high drug content (104.55% ± 7.9%), and physicochemical stability. DSC confirmed the absence of drug-excipient interactions, whereas osmolality (280 ± 4 mOsm/L) and conductance (77.59 ± 1.7 S/m) demonstrated ocular compatibility. To enhance mucoadhesion and prolong corneal residence, chitosan was incorporated into VE-3, yielding CS-VE-3. In vitro release studies showed 81% drug release from VE-3 versus 65% from CS-VE-3, with the latter following Higuchi kinetics, consistent with sustained release. Ex vivo transcorneal studies revealed comparable permeation for VE-3 (43.2% ± 1.14%) and CS-VE-3 (47% ± 1.22%), but distinct drug retention profiles (11.41% ± 0.73% vs. 5.09% ± 0.30%). In vivo pharmacokinetic assessment demonstrated Cmax values of 9.66 ± 3.49 μg/mL (marketed), 10.47 ± 6.43 μg/mL (VE-3), and a four-folds higher 41.67 ± 28.48 μg/mL for CS-VE-3, indicating prolonged corneal contact with chitosan incorporation. Ocular irritation studies confirmed safety and tolerability. The optimized mucoadhesive emulsion offers a promising strategy for sustained ocular delivery of voriconazole, potentially improving therapeutic outcomes in FK management.
This study aimed to design and characterize a new type of self-emulsifying drug delivery system (SEDDS), slowly SEDDS (SL-SEDDS), for long-lasting systemic exposure of tacrolimus (TAC) with reduced nephrotoxicity. TAC-loaded SL-SEDDS (SL-SEDDS/TAC) was prepared by semi-solidifying TAC-loaded SEDDS (SEDDS/TAC) composed of Capryol 90, Cremophor EL, and polyethylene glycol 400 with Geleol. SEDDS samples were evaluated regarding physicochemical and biopharmaceutical properties. Both SEDDS/TAC and SL-SEDDS/TAC formed fine emulsions in water. The dissolution of SEDDS/TAC reached approximately 100% within the initial 30 min in simulated gastric fluid (SGF), and the SL-SEDDS/TAC samples exhibited slower dissolution than SEDDS/TAC in a Geleol content-dependent manner. SL-SEDDS/TAC with a Geleol content of 17.5 wt% showed 25% dissolution in SGF for 2 h, followed by an additional 31% dissolution in simulated intestinal fluid for 10 h. The sample was selected as a favorable SL-SEDDS/TAC for further studies because of its slow and continuous dissolution. Oral SEDDS/TAC and the selected SL-SEDDS/TAC (10 mg-TAC/kg) offered almost identical bioavailability of 18% and 19%, respectively, in rats. Compared with SEDDS/TAC, SL-SEDDS/TAC achieved a 32% decrease in the maximum plasma concentration, a risk factor of nephrotoxicity, from 383 to 262 ng/mL with significantly prolonged mean residence time. In a rat model of acute kidney injury, SL-SEDDS/TAC (10 mg-TAC/kg/day, 3 days) attenuated the elevation of blood nitrogen urea by 33% compared to SEDDS/TAC, suggesting a reduction in nephrotoxic risks. SL-SEDDS could be a promising dosage form to control oral absorption of TAC for effective and safe medication.
Although precipitation of poorly soluble drugs in the gastrointestinal (GI) tract is often considered detrimental to bioavailability, the solid-state nature of the precipitate, either crystalline or amorphous, may critically redefine its impact. Contrasting with reported crystalline precipitates of weakly basic drugs, this study investigates XZP8257 (C27H23Cl2N3O4S), a poorly soluble weakly acidic/zwitterionic compound (BCS II), to explore how GI fluid composition governs precipitate formation and its resulting physicochemical properties. Precipitates were generated in simulated intestinal media with varied bile salt concentrations and pH values. Their solid-state forms were characterized using XRD, SEM, FTIR, and DSC, whereas dissolution performance was evaluated via equilibrium solubility and intrinsic dissolution rate (IDR) measurements. Elevated bile salt concentrations induced a molecular structural transition in XZP8257 and facilitated the formation of crystalline-amorphous mixed precipitates, a phenomenon distinct from the crystalline precipitates typically reported. These novel precipitates exhibited a 5.29- to 22.1-fold increase in equilibrium solubility and a 0.7- to 2.35-fold improvement in IDR compared to the crystalline API. This study reveals that for weakly acidic compounds like XZP8257, precipitate formation in the GI tract can lead to high energy, readily redissolving solid forms, potentially enhancing rather than limiting absorption. This challenges the uniform negative view of precipitation and underscores the necessity of compound-specific precipitate characterization to accurately predict oral absorption, especially in physiologically based biopharmaceutics models.
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 (Km) of 138.6 μM and a maximum transport velocity (Vmax) 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 Tmax 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.
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 (Cmax, Tmax 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.
ABSTRACT 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 R 2 = 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.
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 (Cmax) 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 (ARAUC) 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.
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 letter responds to a recent review on nasal drug delivery systems for brain-targeted therapy. Drawing on first hand experiences as a psychiatrist and migraine patient in Taiwan, the response discusses the practical benefits and challenges of using nasal formulations, such as sumatriptan nasal spray, during ongoing drug shortages. While these formulations offer rapid onset of action, issues related to taste and odor can limit adherence. The letter highlights the potential of advanced technologies like nanocarriers to improve nasal drug delivery and emphasizes the need for patient-centered designs. The correspondence concludes with recommendations for diversifying drug delivery approaches to enhance efficacy and accessibility.
