[Sex differences in hepatobiliary and transplantation surgery]. / Geschlechtsunterschiede in der hepatobiliären und Transplantationschirurgie.

Gender-specific differences in hepatobiliary and transplantation surgery are decisive for the diagnosis, treatment and long-term outcomes. Men exhibit a higher risk of late recurrences and cancer-specific death after liver cancer resection. The emphasis on screening recommendations and ensuring equal access to treatment options are vital to minimize disparities. In kidney and liver transplantations, women are less frequently listed and endure longer waiting times, while men dominate the waiting list. Gender-specific disparities in drug compatibility necessitate differentiated dosing. Further studies are needed to ensure equity in transplantation treatment. Individualized treatment considering these differences can enhance treatment outcomes and the quality of life of patients.

Pharmacokinetics of aspirin: evaluating shortcomings in the literature.

INTRODUCTION: Aspirin is known for its therapeutic benefits in preventing strokes and relieving pain. However, it is toxic to some individuals, and the biological mechanisms causing toxicity are unknown. Limited literature is available on the role of glycine conjugation as the principal pathway in aspirin detoxification. Previous studies have quantified this two-step enzyme reaction as a singular enzymatic process. Consequently, the individual contributions of these enzymes to the kinetics remain unclear. AREAS COVERED: This review summarized the available information on the pharmacokinetics and detoxification of aspirin by the glycine conjugation pathway. Literature searches were conducted using Google Scholar and the academic journal databases accessible through the North-West University Library. Furthermore, the factors affecting interindividual variation in aspirin metabolism and what is known regarding aspirin toxicity were discussed. EXPERT OPINION: The greatest drawback in understanding the pharmacokinetics of aspirin is the limited information available on the substrate preference of the xenobiotic ligase (ACSM) responsible for activating salicylate to salicyl-CoA. Furthermore, previous pharmacokinetic studies did not consider the contribution of other substrates from the diet or genetic variants, to the detoxification rate of glycine conjugation. Impaired glycine conjugation might contribute to adverse health effects seen in Reye's syndrome and cancer.

Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1G93A mouse model of amyotrophic lateral sclerosis following oral administration.

Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114-120 male and female SOD1G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration-time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.

Leonurine: a comprehensive review of pharmacokinetics, pharmacodynamics, and toxicology.

Leonurine is an alkaloid unique to the Leonurus genus, which has many biological activities, such as uterine contraction, anti-inflammation, anti-oxidation, regulation of cell apoptosis, anti-tumor, angiogenesis, anti-platelet aggregation, and inhibition of vasoconstriction. This paper summarizes the extraction methods, synthetic pathways, biosynthetic mechanisms, pharmacokinetic properties, pharmacological effects in various diseases, toxicology, and clinical trials of leonurine. To facilitate a successful transition into clinical application, intensified efforts are required in several key areas: structural modifications of leonurine to optimize its properties, comprehensive pharmacokinetic assessments to understand its behavior within the body, thorough mechanistic studies to elucidate how it works at the molecular level, rigorous safety evaluations and toxicological investigations to ensure patient wellbeing, and meticulously conducted clinical trials to validate its efficacy and safety profile.

Ophiopogonin D: review of pharmacological activity.

Background: Ophiopogon D is an important natural organic compound in Ophiopogon japonicus, which often has significant biological activity. Purpose: The purpose of this review is to systemically summarize and discuss the pharmacological activity and underlying mechanisms of OP-D in recent years. Method: PubMed and Web of Science were searched with the keywords:"Ophiopogon japonicus", "Ophiopogon D" "pharmacology", and "pharmacokinetics". There was no restriction on the publication year, and the last search was conducted on 1 Jan 2024. Results: Emerging evidence suggests that OP-D possess numerous pharmacological activities, including bone protection, cardiovascular protection, immune regulation, anti-cancer, anti-atherosclerosis, anti-inflammatory and anti-NAFLD. Conclusion: OP-D has a potential value in the prevention and treatment of many diseases. We hope that this review will contribute to therapeutic development and future studies of OP-D.

Targeted degradation of KRAS protein in non-small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles.

The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, "undruggable" KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the "undruggable" KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.

Syringin: a naturally occurring compound with medicinal properties.

Syringin, a phenylpropanoid glycoside, is widely distributed in various plants, such as Acanthopanax senticosus (Rupr. et Maxim.) Harms, Syringa reticulata (BL) Hara var. mandshurica (Maxim.) Hara, and Ilex rotunda Thumb. It serves as the main ingredient in numerous listed medicines, health products, and foods with immunomodulatory, anti-tumor, antihyperglycemic, and antihyperlipidemic effects. This review aims to systematically summarize syringin, including its physicochemical properties, plant sources, extraction and separation methods, total synthesis approaches, pharmacological activities, drug safety profiles, and preparations and applications. It will also cover the pharmacokinetics of syringin, followed by suggestions for future application prospects. The information on syringin was obtained from internationally recognized scientific databases through the Internet (PubMed, CNKI, Google Scholar, Baidu Scholar, Web of Science, Medline Plus, ACS Elsevier, and Flora of China) and libraries. Syringin, extraction and separation, pharmacological activities, preparations and applications, and pharmacokinetics were chosen as the keywords. According to statistics, syringin can be found in 23 families more than 60 genera, and over 100 species of plants. As a key component in many Chinese herbal medicines, syringin holds significant research value due to its unique sinapyl alcohol structure. Its diverse pharmacological effects include immunomodulatory activity, tumor suppression, hypoglycemic action, and hypolipidemic effects. Additionally, it has been shown to provide neuroprotection, liver protection, radiation protection, cardioprotection, and bone protection. Related preparations such as Aidi injection, compound cantharidin capsule, and Tanreqing injection have been widely used in clinical settings. Other studies on syringin such as extraction and isolation, total synthesis, safety profile assessment, and pharmacokinetics have also made progress. It is crucial for medical research to deeply explore its mechanism of action, especially regarding immunity and tumor therapy. Meanwhile, more robust support is needed to improve the utilization of plant resources and to develop extraction means adapted to the needs of industrial biochemistry to further promote economic development while protecting people's health.

A study of the pharmacokinetics of clozapine and its metabolites by the dynamics of its distribution in the oral fluid of healthy volunteers.

Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5 mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2 mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130 h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63 ng/mL, 4.53 ± 3.61 h, 57.65 ± 23.77 L/h and 53.58 ± 52.28 h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19 ng/mL, 9.38 ± 9.33 h and 62.67 ± 82.57 h, respectively; of clozapine-N-oxide were 1.15 ± 0.36 ng/mL, 4.53 ± 2.19 h and 19.15 ± 23.11 h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6). CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Translational modeling-based evidence for enhanced efficacy of standard-of-care drugs in combination with anti-microRNA-155 in non-small-cell lung cancer.

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

GLUT5-overexpression-related tumorigenic implications.

Glucose transporter 5 (GLUT5) overexpression has gained increasing attention due to its profound implications for tumorigenesis. This manuscript provides a comprehensive overview of the key findings and implications associated with GLUT5 overexpression in cancer. GLUT5 has been found to be upregulated in various cancer types, leading to alterations in fructose metabolism and enhanced glycolysis, even in the presence of oxygen, a hallmark of cancer cells. This metabolic shift provides cancer cells with an alternative energy source and contributes to their uncontrolled growth and survival. Beyond its metabolic roles, recent research has unveiled additional aspects of GLUT5 in cancer biology. GLUT5 overexpression appears to play a critical role in immune evasion mechanisms, which further worsens tumor progression and complicates therapeutic interventions. This dual role of GLUT5 in both metabolic reprogramming and immune modulation highlights its significance as a potential diagnostic marker and therapeutic target. Understanding the molecular mechanisms driving GLUT5 overexpression is crucial for developing targeted therapeutic strategies that can disrupt the unique vulnerabilities of GLUT5-overexpressing cancer cells. This review emphasizes the complexities surrounding GLUT5's involvement in cancer and underscores the pressing need for continued research to unlock its potential as a diagnostic biomarker and therapeutic target, ultimately improving cancer management and patient outcomes.

Influence of Age, Gender and Body Mass Index on Intravenous Pharmacokinetics of Buprenorphine in Children Undergoing Orthopedic Surgery.

Background: Buprenorphine (BPN) is a widely used analgesic in the pediatric population, although there are few studies on the pharmacokinetics and pharmacodynamics of this drug. Objective: The objective was to characterize the pharmacokinetics of BPN after intravenous administration and analyze the effect of age, gender, weight, height, body mass index (BMI), and drug-drug interactions as covariates. Methods: Ninety-nine children (2-10 years), who underwent orthopedic surgery under regional, general, or combined anesthesia were included. Patients evaluated according to the American Society of Anesthesiologists Physical Status Classification, who received intravenous BPN 2 µg/kg were enrolled. Blood was collected from 1-240 min. Drug plasma concentrations were determined by LC-MS/MS. Population pharmacokinetic parameters were obtained with Monolix 2021R1 software. Pearson's correlation and/or ANOVA were used for statistical analysis. Results: Age was associated with changes in clearance and central compartment volume and the female gender was associated with lower intercompartmental clearance, while BMI modified clearance, central and peripheral compartment volume. Concomitant administration of BPN with fentanyl and dexamethasone produced decreases in clearance. Conclusions: The covariates of sex, age, and BMI are directly related to the increase or decrease in BPN pharmacokinetic parameters.

Development of a UPLC-MS/MS method for quantifying KPT-335 (Verdinexor) in feline plasma for a study of PK.

KPT-335 (Verdinexor) is a novel SINE that potently inhibits the nucleoprotein Exportin 1 (XPO1/CRM1) of tumor cell lines and reduces the replication level of the influenza virus. KPT-335 is mainly used for the treatment of canine tumors. Drugs for the effective treatment of feline tumors are currently unavailable in China. KPT-335 may have potential in the treatment of cat tumors. However, the effects of KPT-335 in cats are unreported, and no relevant methodology has been established for pharmacokinetic studies. In this study, a UPLC-MS/MS method was developed to determine KPT-335 concentrations in cat plasma, followed by pharmacokinetic studies. Briefly, plasma proteins are precipitated with acetonitrile, and the supernatant was collected for detection after centrifugation. The linearity for KPT-335 in cat plasma was in the range of 5-1,000 ng/mL. Satisfactory accuracy and precision were obtained. The intra-day accuracy was between -4.10% and 10.48%, the precision was ≤4.65%; the inter-day accuracy was between -0.11% and 8.09%, and the precision was ≤5.85%. Intra-day and inter-day accuracy and precision were within regulatory limits. The results of preliminary pharmacokinetic studies were as follows: Tmax was 1.46 ± 0.51 h; Cmax was 239.54 ± 190.60 ng·mL-1; T1/2 was 5.16 ± 2.30 h; AUC0-t was 1439.85 ± 964.64 ng·mL-1·h. The AUC0-∞ was 1589.82 ± 1003.75 ng·mL-1·h. The purpose of this study was to develop a rapid and simple UPLC-MS/MS method to detect KPT-335 concentration in cat plasma and to conduct preliminary pharmacokinetic studies to support the future application of KPT-335 in felines.

Efflux ABC transporters in drug disposition and their posttranscriptional gene regulation by microRNAs.

ATP-binding cassette (ABC) transporters are transmembrane proteins expressed commonly in metabolic and excretory organs to control xenobiotic or endobiotic disposition and maintain their homeostasis. Changes in ABC transporter expression may directly affect the pharmacokinetics of relevant drugs involving absorption, distribution, metabolism, and excretion (ADME) processes. Indeed, overexpression of efflux ABC transporters in cancer cells or bacteria limits drug exposure and causes therapeutic failure that is known as multidrug resistance (MDR). With the discovery of functional noncoding microRNAs (miRNAs) produced from the genome, many miRNAs have been revealed to govern posttranscriptional gene regulation of ABC transporters, which shall improve our understanding of complex mechanism behind the overexpression of ABC transporters linked to MDR. In this article, we first overview the expression and localization of important ABC transporters in human tissues and their clinical importance regarding ADME as well as MDR. Further, we summarize miRNA-controlled posttranscriptional gene regulation of ABC transporters and effects on ADME and MDR. Additionally, we discuss the development and utilization of novel bioengineered miRNA agents to modulate ABC transporter gene expression and subsequent influence on cellular drug accumulation and chemosensitivity. Findings on posttranscriptional gene regulation of ABC transporters shall not only improve our understanding of mechanisms behind variable ADME but also provide insight into developing new means towards rational and more effective pharmacotherapies.

A randomized phase 1 study of safety, tolerability, and pharmacokinetics of MK-1088, a novel dual adenosine receptor antagonist, in healthy adult participants.

This phase 1 first-in-human study evaluated the safety, tolerability, and pharmacokinetics of MK-1088, a novel, small-molecule dual inhibitor of adenosine A2A and A2B receptors. Healthy adult participants were enrolled in two panels (n = 8 each) and randomly assigned to receive MK-1088 (n = 6) or placebo (n = 2) orally in each of five treatment periods. Participants in panel A received single ascending doses of MK-1088 at 1, 10, 50, and 150 mg or placebo in a fasted or fed (50 mg only) state. Participants in panel B received MK-1088 at 3, 25, 100, and 224 mg or placebo in a fasted state. Primary objectives were to evaluate safety, tolerability, and plasma pharmacokinetics following a single dose of MK-1088. The secondary objective was to evaluate the effects of a high-fat meal on pharmacokinetics. All participants (n = 16) completed the study (median age: 33 years [range: 20-43]; all were male). Treatment-related adverse events (AEs) occurred in 1 of 6 (17%), 4 of 6 (67%), 4 of 6 (67%), and 2 of 6 (33%) participants after receiving MK-1088 at 3, 25, 100, and 224 mg, respectively. No serious AEs or deaths due to any cause occurred. MK-1088 was rapidly absorbed after a single dose; half-life was ~ 11 h in the 100-224 mg dose range. The target concentration at 12 h (> 0.3 µM) was exceeded at the 50-mg dose level. MK-1088 plasma pharmacokinetics increased dose proportionately. A high-fat meal did not significantly affect pharmacokinetics at the 50-mg dose. MK-1088 was well tolerated and demonstrated dose-proportional pharmacokinetic properties that were not affected by a high-fat meal.

Interaction of a caffeine overdose with clinical doses of contraceptive ethinyl estradiol in a young woman.

Aim: The overdose of caffeine, a cytochrome P450 1A2 probe, in young women has become a problem. The aim of this study was to evaluate possible drug interactions between intentionally overdosed caffeine (12 g) and oral contraceptive doses of ethinyl estradiol prescribed to a young woman in a suicide attempt. Methods: The serum concentrations of caffeine in the patient and the time-dependent ethinyl estradiol inhibition of caffeine oxidation in vitro were evaluated. Results: The serum concentration of caffeine 4 h after overdose was 136 µg/mL; from the data obtained between 4 and 28 h after overdose, the half-life was estimated to be 33 h, which is many times larger than the normal value. Prescribed ethinyl estradiol prolonged caffeine elimination in vivo and inhibited paraxanthine formation, as evidenced by the low serum concentrations. In human liver microsomes, ethinyl estradiol (50 nM) inhibited half of caffeine N 3 -demethylation. Pre-incubation of human liver microsomes with ethinyl estradiol resulted in a powerful time-dependent inhibitory effect on caffeine N 3 -demethylation in human liver microsomes. Conclusion: These results suggest that a prescription history of contraceptives at clinical doses may have a strong effect on the pharmacokinetics of overdosed caffeine in young women, resulting in dangerous drug interactions.

Exploring Montelukast in Dogs: A Preliminary Pharmacokinetic Study Following Oral Administration under Fasted and Fed Conditions.

This study investigates the pharmacokinetics (PK) of montelukast (MTK), a cysteinyl leukotriene receptor antagonist increasingly being considered in veterinary medicine. In dogs, MTK has found indications mainly for treating atopic dermatitis as an off-label use. Six male Labrador dogs underwent a single oral administration of MTK (40mg/dog) in both fasted and fed conditions according to an open, single-dose, two-treatment, two-phase, cross-over design, with a washout period of one week. Blood was withdrawn to heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24hr. MTK plasma concentrations were quantified using a validated HPLC method, and the data were analysed using PKanalixTM software with a non-compartmental approach. Concentrations remained quantifiable at 24hr after administration, under both conditions. No significant differences were observed in the PK parameters between the fasted and fed states. MTK was relatively eliminated slowly, with t1/2 values of 8.10 and 7.68hr after fasted and fed states, respectively. The attainment of maximum concentration (Cmax) occurred at a Tmax of 4hr, with mean values of 1.98µg/mL and 2.80µg/mL under fasted and fed conditions, respectively. Given the unknown therapeutic range of MTK in dogs and the absence of controlled studies proving its efficacy in this species, further dosing adjustments and refinements should be considered based on both the current PK data and the need to establish an effective therapeutic range, if present. Future research should focus on efficacy studies, multiple-dose investigations, and pharmacodynamic assessments to evaluate the suitability of MTK use in dogs.

The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Ritlecitinib, a Janus Kinase 3 and Tyrosine-Protein Kinase Family Inhibitor, in Humans.

Ritlecitinib is an oral once-daily irreversible inhibitor of Janus kinase 3 and tyrosine-protein kinase family being developed for the treatment of moderate-to-severe alopecia areata. This study examined the disposition of ritlecitinib in male participants following oral and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters and characterize metabolite profiles. The results indicated ritlecitinib had a systemic clearance of 43.7 L/h, a steady state volume of distribution of 73.8 L, extent of absorption of 89%, time to maximum plasma concentration of ~0.5 hour, and absolute oral bioavailability of 64%. An observed long terminal half-life of total radioactivity was primarily attributed to ritlecitinib binding to plasma albumin. Ritlecitinib was the main circulating drug species in plasma (~30%) with one major pharmacologically inactive cysteine conjugated metabolite (M2) at >10%. Oxidative metabolism (fractional clearance 0.47) and glutathione related conjugation (fractional clearance 0.24) were the primary routes of elimination for ritlecitinib with the greatest disposition of radioactivity shown in the urine (~71%). In vitro phenotyping indicated ritlecitinib cytochrome P450 fraction of metabolism assignments of 0.29 for CYP3A, 0.09 for CYP2C8, 0.07 for CYP1A2, and 0.02 for CYP2C9. In vitro phenotyping in recombinant human glutathione S-transferases indicated ritlecitinib was turned over by a number of cytosolic and microsomal enzyme isoforms. Significance Statement This study provides a detailed understanding of the disposition and metabolism of ritlecitinib, a JAK3 and TEC family kinase inhibitor for alopecia areata, in humans, as well as characterization of clearance pathways and PK of ritlecitinib and its metabolites. As an AMS-based ADME study design, we have expanded on reporting the standard ADME endpoints, providing key pharmacokinetic parameters like clearance, volume of distribution and bioavailability allowing for a more comprehensive understanding of drug disposition.

Simultaneous estimation of paclitaxel and bortezomib via LC-MS/MS: pharmaceutical and pharmacokinetic applications.

Aim & Objective: This study evaluates the potential of combining paclitaxel (PTX) and bortezomib (BTZ) for breast cancer therapy. Materials & Methods: The nanoformulation was optimized via Box-Behnken Design (BBD), with method validation adhering to US-FDA guidelines. Results: Multiple reaction monitoring transitions for PTX, BTZ and internal standard were m/z 855.80→286.60, 366.80→226.00 and 179.80→110.00, respectively. Elution done on C18 Luna column with 0.1% FA in MeOH:10 mM ammonium acetate. The size of nanoformulation was 133.9 ± 1.97 nm, PDI 0.19 ± 0.01 and zeta potential -19.20 ± 1.36 mV. Pharmacokinetics showed higher Cmax for PTX-BTZ-NE (313.75 ± 10.71 ng/ml PTX, 11.92 ± 0.53 ng/ml BTZ) versus free PTX-BTZ (104 ± 13.06 ng/ml PTX, 1.9 ± 0.08 ng/ml BTZ). Conclusion: Future findings will contribute to the treatment of breast cancer using PTX and BTZ.

[Box: see text].