Search Results (131)

Background/Objectives: Type 2 diabetes is a group of metabolic disorders whose pathophysiological outcome is sustained hyperglycemia. Several medications are available for the treatment. SGLT2 simultaneously inhibits glucose and sodium reabsorption in the renal proximal tubule, resulting in urinary glucose excretion. This study assessed the pharmacokinetic profiles of two empagliflozin 25 mg drug products under fasting conditions in healthy Mexican subjects to establish bioequivalence. Methods: This was a randomized, open-label, two-way crossover, single-dose, prospective study with a 7-day washout period. Eligible subjects were healthy adult Mexican volunteers. The drugs were dosed orally, according to the randomization, after 10 h of fasting and 4 h before breakfast, with 250 mL of 10% glucose solution at room temperature. Serial blood samples were collected before and after dosing. Empagliflozin concentrations were analyzed using high-performance liquid chromatography–tandem mass spectrometry. Results: A total of 32 subjects were enrolled, and 30 completed the study. Pharmacokinetic parameters C_max, t_max, AUC_0–t, AUC _0–∞, and t_½ of empagliflozin for test and reference formulation, expressed as mean ± SD, were 578.28 ± 125.60 ng/mL, 2.72 ± 0.85 h, 4370.88 ± 769.50 ngh/mL, 4423.93 ± 776.02 ngh/mL, 7.62 ± 0.83 h, and 593.99 ± 156.78 ng/mL, 2.86 ± 1.00 h, 4313.24 ± 885.02 ngh/mL, 4368.04 ± 887.75 ngh/mL, and 7.61 ± 0.68 h, respectively. The 90% CI for C_max, AUC_0–t, and AUC _0–∞ were 98.30 [92.72–104.22], 101.72 [98.77–104.77], and 101.64 [98.73–104.63], respectively. Serious adverse events were not observed. Conclusions: Our study demonstrated bioequivalence between the empagliflozin formulations tested in healthy subjects under fasting conditions. Full article

Chronic kidney disease (CKD) affects more than 10% of the world’s population, increasing the risk of cardiovascular disease and mortality. Background: Nephroprotective interventions can reduce the risk of end-stage renal disease, delay the time to dialysis, and prolong life. However, there is ongoing debate about the effectiveness of combining amino acid ketoanalogues (KAA) with a low-protein diet (LPD) to slow CKD progression. This study aimed to retrospectively analyze kidney function outcomes after a 6-month KAA+LPD regimen in patients with CKD. Methods: The analysis included results from 38 non-dialyzed patients (12 F, 26 M; age 64.0 ± 13.6 years) with stable CKD in stages G4 to G5, who followed LPD with KAA (Ketosteril, Fresenius Kabi) treatment as part of the Polish National Health Fund Ketosteril Drug Program. Results: No significant change in estimated glomerular filtration rate (eGFR) was observed during 6 months of KAA+LPD therapy. However, eGFR increased or decreased in half of the patients (p < 0.001), and this change was associated only with initial protein intake and urinary phosphate excretion. Initial high phosphate excretion was independently associated with an increase in eGFR, and initial phosphaturia > 0.5 g/24 h identified eGFR improvement (sensitivity 84.2%; specificity 57.9%; AUC 0.712; p = 0.018) in CKD patients who started KAA+LPD treatment. Conclusions: Six-month treatment with KAA+LPD may be associated with stabilization of kidney function in patients with CKD stages G4-G5. The individual effect of KAA+LPD on renal function may be related to the initial protein intake level and urinary phosphate excretion. Further studies are needed to validate these findings across larger patient populations with a broader spectrum of symptoms. Full article

Tuberculosis (TB) remains a critical global public health challenge, requiring therapeutic strategies that ensure high cure rates while minimizing bacillary transmission. The 2022 World Health Organization (WHO) update for drug-resistant TB treatment prioritized a novel, 6-month, all-oral regimen composed of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) as the preferred treatment for rifampicin- and multidrug-resistant tuberculosis (RR-/MDR-TB). However, the clinical success of this shortened therapy is intrinsically linked to managing complex drug–drug interactions and treatment-emergent adverse effects which may necessitate regimen modifications. This article provides a comprehensive pharmacological review of the BPaLM components, detailing their mechanisms of action, pharmacokinetics (absorption, metabolism, and excretion), and safety profiles. Furthermore, we analyze critical drug interactions—including those involving food and antacids—and provide evidence-based guidance for special clinical populations, such as pregnant and breastfeeding women, and patients with hepatic or renal impairment. Mastery of these pharmacological nuances is essential for clinicians to optimize treatment adherence and ensure improved treatment completion rates and reduced resistance emergence. Full article

Renal organic anion transporters 1 (OAT1) and 3 (OAT3) mediate the excretion of endogenous metabolites and xenobiotics. Flavonoids interact significantly with these transporters, but the structural determinants—especially regarding in vivo phase II metabolism—remain unclear. This review integrates recent cryogenic electron microscopy (cryo-EM) structural biology and transporter kinetics to delineate the molecular basis of flavonoid–OAT interactions. We highlight phase II metabolites as key in vivo effectors. Structurally, OAT1 strictly favors compact, planar anionic scaffolds, whereas OAT3 accommodates bulkier, conjugated forms. Crucially, flavonoids exert a “double-edged” toxicological effect: high-affinity OAT inhibition risks herb–drug interactions, yet competitively limits the tubular uptake of nephrotoxins. Furthermore, disease states and post-translational regulation reshape these interactions. By bridging structural insights with biomarker-guided pharmacokinetics, we propose a mechanistic framework to improve the precise safety assessment of flavonoid-containing therapeutics. Full article

Background: Hyperuricemia (HUA) is a metabolic disorder that severely threatens human health. Chronic uric acid (UA) overload promotes the progression of tubulointerstitial fibrosis (TIF), leading to impaired UA excretion. Our previous studies identified HIPK2 inhibitor XRF-1021, which exhibits robust anti-TIF activity and lowers UA levels in vivo. This study aimed to elucidate its UA-lowering mechanism and therapeutic potential for HUA. Methods: Uricase and xanthine oxidase (XOD) assays were performed to assess effects on UA degradation/production. HEK293T cells transiently expressing UA transporters and gene-knockdown rats were used to evaluate transporter inhibition, while HK-2 cells were analyzed by Western blot. Pharmacokinetics were characterized in rats. Efficacy was tested in potassium oxonate-induced acute HUA rats, diet/adenine-induced chronic HUA quails, and adenine-induced mice with HUA secondary to TIF. Maximum tolerated dose and long-term toxicity were assessed in rats. Results: XRF-1021 neither activated uricase nor inhibited XOD, indicating no direct effect on UA catabolism or synthesis. Instead, XRF-1021 inhibited URAT1 and GLUT9, reducing renal UA reabsorption, while sparing OAT3, OAT4, and ABCG2 activity and upregulating OAT3 and NPT4, suggesting minimal risk of disrupting drug or uremic toxin handling. XRF-1021 showed dose-dependent systemic exposure in rats, lowered serum UA, and provided renal protection in vivo. LD₅₀ values were 2345.4 mg/kg (male) and 1078.9 mg/kg (female), with no obvious toxicity after long-term dosing. Conclusions: XRF-1021 lowers UA by inhibiting URAT1 and GLUT9 to enhance renal UA excretion and provides kidney protection, supporting XRF-1021 as a promising candidate for HUA therapy. Full article

Objective: The therapeutic efficacy of the classic antibiotic combination trimethoprim/sulfamethoxazole (TMP/SMZ) is often limited by the significant pharmacokinetic mismatch. In this study, a polyethylene glycol-polylactic-co-glycolic acid (PEG-PLGA) nanodelivery system was employed to improve the pharmacokinetic matching of TMP and SMZ. The investigation also evaluated the enhanced in vivo antibacterial efficacy of this formulation. Methods: Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) was employed to systematically characterize the absorption, distribution, and excretion profiles of PEG-PLGA-loaded TMP nanoparticles (NPs) in rats. In vitro antibacterial activity was assessed against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vivo efficacy and biosafety of the TMP NPs/SMZ regimen were evaluated using a murine E. coli infection model via survival monitoring, biochemical assays, and histopathology. Results: Pharmacokinetic analysis revealed that TMP NPs achieved a relative bioavailability of 193.05% and extended the elimination half-life by 3.37-fold compared to free TMP. Tissue distribution showed significantly increased drug accumulation in the liver, spleen, and kidneys, with renal clearance as the primary excretion pathway (73.89%). In vitro, the nano-formulation reduced the minimum inhibitory concentration (MIC) by 2-4-fold and shortened the bactericidal duration from 12 to 8 h. In vivo, the TMP NPs/SMZ combination significantly improved survival rates, accelerated recovery, and alleviated infection-induced organ damage without systemic toxicity. Conclusions: This nanotechnology-based strategy effectively aligns the pharmacokinetics of TMP and SMZ, prolongs their synergistic window, and enhances biosafety, offering a viable approach to revitalize classic antibiotic combinations. Full article

Background/Objectives: Dapagliflozin is an SGLT2 inhibitor prescribed for the management of type 2 diabetes mellitus. The drug lowers blood glucose levels by increasing urinary glucose excretion (UGE). Despite established efficacy, dapagliflozin demonstrates significant inter-individual variability in pharmacokinetics (PK) and pharmacodynamics (PD), with potential impact on treatment outcomes. Methods: To evaluate the sources of variability and to support patient stratification and model-informed individualized therapy, we developed a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of dapagliflozin using curated data from 28 clinical studies. This framework integrates absorption, distribution, metabolism, excretion, and pharmacodynamics, and accounts for key determinants of variability including renal and hepatic function, and food effects. Results: The simulations reproduced dose-dependent pharmacokinetics with predicted C_max and AUC values typically within 10–15% of observed data. Renal impairment reduced UGE by 40–60% despite modest changes in plasma exposure, while hepatic impairment produced only small shifts in PK and PD. The model also reproduced the fed-state reduction of peak concentrations, consistent with the 30–50% decrease reported clinically. Conclusions: All model files, code, and curated datasets are openly available in line with FAIR standards and Open Science practices, enabling transparent and reproducible analyses and providing a mechanistic basis for individualized therapy in type 2 diabetes. Full article

Background/Objectives: The short-term effect of Janus kinase inhibitors (JAKis) on renal function in patients with rheumatoid arthritis (RA) was examined in a hypothesis-generating, exploratory study. Methods: RA patients treated with JAK inhibitors and, as a control group, those receiving golimumab and continuing treatment for one or more years were enrolled. They were monitored every 3 months for disease activity using the Simplified Disease Activity Index (SDAI), functional capacity using the Health Assessment Questionnaire Disability Index (HAQ), and renal function using the estimated glomerular filtration rate (eGFR) calculated from creatinine (Cr) and cystatin C (CysC). Patients were categorized by medication, and average values were computed. Two groups for each drug were then compared statistically. Results: A total of 144 patients were analyzed: 24 on tofacitinib, 43 on baricitinib, 21 on upadacitinib, 21 on filgotinib, and 35 on golimumab. Background factors did not differ significantly among groups. Improvements in CDAI and HAQ at any time point also showed no significant differences. eGFR based on Cr showed a significant decline in the baricitinib and filgotinib groups at one year after starting JAKi treatment compared with the other JAKi groups; however, there was no significant difference when using CysC. Conclusions: These results indicate that there is no significant difference in renal function decline among the JAKi drugs over a short period, despite differences in their metabolic pathways and renal excretion patterns. Full article

Background/Objectives: This study aimed to develop an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for quantifying amantadine (AMA) in rat plasma and to investigate its pharmacokinetics under simulated high-altitude hypoxia, contrasting its behavior with that of its structural analog memantine (MEM). Methods: The method entailed using memantine (MEM) as an internal standard. Sample preparation involved protein precipitation, followed by gradient elution with detection via positive electrospray ionization and selective reaction monitoring (SRM). The method validation complied with the International Conference on Harmonization (ICH) M10 guidelines. Pharmacokinetic studies were conducted in rats exposed to either low altitude (1500 m) or simulated high altitude (6500 m) after a single oral dose of AMA (10 mg/kg). Results: The assay demonstrated linearity from 5 to 1000 µg/L, with accuracy, precision, recovery, and stability all meeting the respective acceptance criteria. Hypoxia did not significantly alter systemic exposure to AMA, as measured by parameters such as the area under the concentration–time curve (AUC), maximum concentration (Cmax), and apparent clearance (CLz/F). However, hypoxia prolonged the elimination half-life by 55% and increased the variance in the mean residence time. This finding contrasts sharply with our previous results on MEM under identical hypoxic conditions, which showed a 72.15% increase in AUC and a 41.99% decrease in CLz/F. Conclusions: A robust UPLC-MS/MS method for quantifying AMA was successfully established. AMA exhibits unique pharmacokinetic resilience to acute hypoxia, characterized by increased variability in elimination without changes in overall exposure. This profile starkly differs from the heightened exposure and reduced clearance observed for drugs like MEM, which are predominantly cleared by hepatic metabolism (under the studied conditions). These findings are consistent with the concept that a drug’s primary elimination pathway (renal excretion vs. hepatic metabolism) critically determines its pharmacokinetic susceptibility to hypoxic stress. Full article

Physiologically based pharmacokinetic (PBPK) models are widely used in the context of personalized medicine, as they allow for the evaluation of dosing schedules and routes of administration by predicting absorption, distribution, metabolism and excretion (ADME) of drugs in biological systems. Traditionally, PBPK models have been developed and applied at the population level, enabling the characterization of predefined cohorts, which remains limited in supporting true precision dosing. In this review, we explored the increasingly common shift from population-based to individual PBPK modelling, where individuals are modelled as virtual twins (VTs). Through the inclusion of additional patient-specific data, such as demographic, physiological, phenotypic and genotypic information, models can be personalized, moving beyond traditional one-size-fits-all strategies. Overall, incorporating individual patient data (e.g., septic, psychiatric, cardiac, or neonatal populations) improves model performance. Physiological parameters, particularly renal function, show strong potential given their role in drug elimination, while demographic variables enhance predictive accuracy in certain studies. In contrast, the benefits of including cytochrome P450 (CYP) phenotypic and genotypic data remain inconsistent. We further emphasize methodologies used to evaluate model performance, with a focus on clinical validation through comparisons between predicted and observed concentration-time profiles. Key challenges, including limited sample sizes and data availability, that may compromise predictive precision, are also discussed. Finally, we highlight the potential integration of PBPK-based VTs into broader digital twin frameworks as a promising path toward clinical translation, while acknowledging the critical barriers that must be addressed to enable routine clinical implementation. Full article

Acyclovir is an antiviral drug effective against infections caused by herpes simplex and varicella zoster viruses. It is given intravenously to treat serious infections such as herpes encephalitis. High acyclovir concentrations could cause toxicity, observed mainly as nephrotoxicity and, to a lesser extent, neurotoxicity. Acyclovir nephrotoxicity is primarily attributed to the crystallization of acyclovir within the renal tubules, although additional mechanisms may also contribute. However, the mechanism of acyclovir-induced neurotoxicity is unknown. Acyclovir is mainly eliminated from the body through renal excretion; however, around 15–20% of acyclovir is metabolized subsequently by alcohol and aldehyde dehydrogenase to the main metabolite 9-carboxymethoxymethylguanine (CMMG), and around 2% is metabolized by aldehyde oxidase to the minor metabolite, 8-hydroxyl acyclovir. It has been suggested that CMMG levels above 10 µmol/mL in the serum and 1 µmol/mL in the cerebrospinal fluid are highly associated with neurotoxicity. Studies have shown that there is a potential contribution of CMMG to acyclovir-induced neurotoxicity and of the acyclovir aldehyde to nephrotoxicity. In this narrative review, we approach the topic of acyclovir metabolites and their association with acyclovir toxicity. Moreover, we identify the research gap of the mechanisms by which these metabolites contribute to toxicity. Full article

Background/Objectives: Plant-derived diuretics are attracting increasing interest due to their promising efficacy and improved safety profile compared with synthetic drugs. This study aimed to characterize the phytochemical composition of Astragalus boeticus (A. boeticus) extracts, evaluate their diuretic activity, and assess the oral safety of their main phenolic compound. Methods: Aqueous (AQE) and hydroethanolic (EtOHE) extracts were analyzed using LC–MS/MS, while in silico toxicity prediction of trans-resveratrol was performed using ProTox-II and ADMETlab 2.0. Diuretic activity was evaluated in male Wistar rats (n = 24) divided into four groups: control (distilled water, 10 mL/kg), furosemide (10 mg/kg), AQE (300 mg/kg), and EtOHE (300 mg/kg). Urine and plasma samples were collected after 15 days to determine electrolyte concentrations, creatinine level, creatinine clearance, and hepatic enzyme profile. Results: LC–MS/MS profiling identified fourteen phenolic compounds, with trans-resveratrol (270 µg/g in AQE) being the most abundant, followed by cyanidin-3-O-glucoside and gentisic acid. In silico assessments revealed no hepatotoxic, mutagenic, or neurotoxic effects of trans-resveratrol. Both extracts significantly enhanced urinary output, chloride excretion, and creatinine clearance, while maintaining stable renal and hepatic biochemical parameters, indicating potent diuretic activity without toxicity. Conclusions: A. boeticus extracts demonstrate strong diuretic potential associated with a favorable safety profile, likely linked to their phenolic composition dominated by trans-resveratrol. These findings support the use of A. boeticus as a natural and safe diuretic source. Further investigation is recommended to elucidate its pharmacological mechanisms and therapeutic relevance. Full article

Acute kidney injury (AKI) is a frequent and severe complication in trauma patients, affecting up to 28% of intensive care unit (ICU) admissions and contributing significantly to morbidity, mortality, and long-term renal impairment. Trauma-related AKI (TRAKI) arises from diverse mechanisms, including hemorrhagic shock, ischemia–reperfusion injury, systemic inflammation, rhabdomyolysis, nephrotoxicity, and complex organ crosstalk involving the brain, lungs, and abdomen. Pathophysiologically, TRAKI involves early disruption of the glomerular filtration barrier, tubular epithelial injury, and renal microvascular dysfunction. Inflammatory cascades, oxidative stress, immune thrombosis, and maladaptive repair mechanisms mediate these injuries. Trauma-related rhabdomyolysis and exposure to contrast agents or nephrotoxic drugs further exacerbate renal stress, particularly in patients with pre-existing comorbidities. Traditional markers such as serum creatinine (sCr) are late indicators of kidney damage and lack specificity. Emerging structural and stress response biomarkers—such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), C-C motif chemokine ligand 14 (CCL14), Dickkopf-3 (DKK3), and the U.S. Food and Drug Administration (FDA)-approved tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein 7 (TIMP-2 × IGFBP-7)—allow earlier detection of subclinical AKI and better predict progression and the need for renal replacement therapy. Together, functional indices like urinary sodium and fractional potassium excretion reflect early microcirculatory stress and add clinical value. In parallel, risk stratification tools, including the Renal Angina Index (RAI), the McMahon score, and the Haines model, enable the early identification of high-risk patients and help tailor nephroprotective strategies. Together, these biomarkers and risk models shift from passive AKI recognition to proactive, personalized management. A new paradigm that integrates biomarker-guided diagnostics and dynamic clinical scoring into trauma care promises to reduce AKI burden and improve renal outcomes in this critically ill population. Full article

Background: Physiologically based pharmacokinetic (PBPK) models utilize computer-based simulations to predict the pharmacokinetics of drugs. By using mathematical modeling techniques consisting of differential equations to simulate blood flow, tissue compositions, and organ properties, the pharmacokinetic properties of drugs can be better understood. Specifically, PBPK models can provide predictive information about drug absorption, distribution, metabolism, and excretion (ADME). The information gained from PBPK models can be useful in both drug discovery, development, and regulatory science. PBPK models can help to address some of the ethical dilemmas that arise during the drug development process, particularly when examining patient populations where testing a new drug may have significant ethical concerns. Patient populations where significant physiological change (i.e., pregnancy, pediatrics, geriatrics, organ impairment populations, etc.) and pathophysiological influences resulting in PK changes can also benefit from PBPK modeling. Additionally, PBPK models can be utilized to predict variations in drug metabolism resulting from genetic polymorphisms, age, and disease states. Methods: In this mini-review, we examine the various applications of PBPK models in drug metabolism. Current research articles related to drug metabolism in genetics, life-stages, and disease states were reviewed. Results: Several key factors in genetics, life-stage, and disease states that affect metabolism in PBPK models are identified. In genetics, the role of CYP enzymes, genetic polymorphisms, and ethnicity may influence metabolism. Metabolism generally changes over time from neonate, pediatric, adult, geriatric, and perinatal populations. Disease states such as renal and hepatic impairment, weight and other acute and chronic diseases also can also alter metabolism. Several examples of PBPK models applying these physiological changes have been published. Conclusions: The utilization and recognition of these specific areas in PBPK modeling can aid in personalized dosing strategy, clinical trial optimization, and regulatory submission. Full article

Hyperuricemia has been increasingly recognized as a modifiable contributor to chronic kidney disease (CKD) progression. Although the traditional classification of hyperuricemia distinguished between renal underexcretion and renal overload types, recent studies suggest that hyperuricemia in patients with CKD can result from heterogeneous excretory defects, including glomerular under-filtration and tubular over-reabsorption. These distinct phenotypes may drive divergent renal injury mechanisms. Experimental and clinical data reveal that monosodium urate crystals and soluble uric acid independently induce renal damage through oxidative stress, inflammasome activation, and endothelial dysfunction. Furthermore, clinical investigations showed inconsistent associations between serum uric acid levels and renal outcomes, suggesting that serum levels alone may not fully reflect urate-related renal risk. This has prompted increasing interest in uricosuric agents, particularly the selective urate reabsorption inhibitors (SURIs), which target tubular urate handling. Urate transporter 1 inhibitors have shown promise in enhancing urinary uric acid excretion and potentially preserving kidney function, especially in patients with CKD. In this review, we summarize the current evidence linking the emerging pathophysiological classification of hyperuricemia, mechanisms or urate-induced kidney injury, and therapeutic interventions. These insights may inform individualized approaches to urate-lowering therapy in CKD and support future research into phenotype-guided treatment strategies. Full article