A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
The end of the list has been reached or no journals were found for your choice.
Similar Journals
Journal Cover
European Journal of Drug Metabolism and Pharmacokinetics
Journal Prestige (SJR): 0.338
Citation Impact (citeScore): 1
Number of Followers: 5  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0378-7966 - ISSN (Online) 2107-0180
Published by Springer-Verlag Homepage  [2468 journals]
  • Pharmacokinetic–Pharmacodynamic Modelling in Hemophilia A: Relating
           Thrombin and Plasmin Generation to Factor VIII Activity After
           Administration of a VWF/FVIII Concentrate

    • Free pre-print version: Loading...

      Abstract: Background Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay. Objective The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic–pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters. Methods Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P®). The predictive performance of the previously developed pharmacokinetic–pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed. Results The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC50 and Emax values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%). Conclusion Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.
      PubDate: 2024-02-17
       
  • Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor
           Antagonist Ocedurenone (KBP-5074) in Individuals with Moderate Hepatic
           Impairment

    • Free pre-print version: Loading...

      Abstract: Background and Objectives Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment. Methods This study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child–Pugh B, score 7–9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography–tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis. Results Following a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (Tmax) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (Cmax), the disposition of ocedurenone appeared to be biphasic. The geometric mean t1/2 values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5–26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas Cmax was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants. Conclusions Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and Cmax do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. Clinical Trial Identifier (www.clinicaltrials.gov) NCT04534699.
      PubDate: 2024-02-08
       
  • Optimizing Antibiotic Therapy for Intravenous Drug Users: A Narrative
           Review Unraveling Pharmacokinetics/Pharmacodynamics Challenges

    • Free pre-print version: Loading...

      Abstract: Abstract Intravenous drug users (IVDUs) face heightened susceptibility to life-threatening gram-positive bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA). While the standard antibiotic dosing strategies for special patients, such as obese or critically ill individuals, are known to be inadequate, raising concerns about treatment efficacy, a similar sort of understanding has not been assessed for IVDUs yet. With this in mind, this review examines the pharmacokinetic/pharmacodynamic characteristics of antibiotics commonly used against gram-positive bacteria in IVDUs. Focusing on daptomycin, vancomycin, teicoplanin, aminoglycosides, and the novel lipoglycopeptide dalbavancin, the study reveals significant pharmacokinetic variations in IVDUs, suggesting the need for personalized dosing. Concomitant opioid substitution therapy and other factors, such as malnutrition, contribute to altered pharmacokinetics/pharmacodynamics, emphasizing the importance of targeted therapeutic drug monitoring. Overall, our study calls for increased awareness among clinicians regarding the unique pharmacokinetic/pharmacodynamic challenges in IVDUs and advocates for tailored antibiotic dosing strategies to enhance treatment outcomes in this marginalized population.
      PubDate: 2024-02-08
       
  • Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability:
           In Vitro and In Silico Preliminary Study

    • Free pre-print version: Loading...

      Abstract: Background and Objective Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.5 and 6.5) and the interactions of tested substances with skin ATP-binding cassette (ABC) transporters in silico. Methods After the incubation period, the clindamycin hydrochloride concentrations in both compartments were determined spectrophotometrically, and the apparent permeability coefficients (Papp) were calculated. Vienna LiverTox web service was used to predict the interactions of clindamycin and bile acids with potential drug transporters located in human skin. Results Both CA and DCA at the highest studied concentration of 100 μM in the tested solutions increased the skin-PAMPA membrane permeability of clindamycin hydrochloride. This effect was more pronounced for CA and at a higher studied pH value of 6.5, which is characteristic of most dermatological indications treated with topical clindamycin preparations. Clindamycin transport may also be mediated by ABC transporters located in skin and facilitated in the presence of bile acids. Conclusions The results of this study provide a solid foundation for further research directed at the improvement of topical formulations using bile acids as penetration-enhancing excipients, as well as the therapeutic efficacy of clindamycin hydrochloride.
      PubDate: 2024-02-08
       
  • Improved Pharmacokinetic and Pharmacodynamic Profile of
           Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and
           Clomipramine in Animal Models

    • Free pre-print version: Loading...

      Abstract: Background and Objectives Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts. Methods In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out. Results Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (Cmax), elimination half-life (t1/2), and area under the concentration-time curve (AUC)  in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine. Conclusions Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.
      PubDate: 2024-01-03
       
  • Neural Network Models for Predicting Solubility and Metabolism Class of
           Drugs in the Biopharmaceutics Drug Disposition Classification System
           (BDDCS)

    • Free pre-print version: Loading...

      Abstract: Background and Objective The biopharmaceutics drug disposition classification system (BDDCS) categorizes drugs into four classes on the basis of their solubility and metabolism. This framework allows for the study of the pharmacokinetics of transporters and enzymatic metabolization on biopharmaceuticals, as well as drug–drug interactions in the body. The objective of the present study was to develop computational models by neural network models and structural parameters and physicochemical properties to estimate the class of a drug in the BDDCS system. Methods In this study, deep learning methods were utilized to explore the potential of artificial and convolutional neural networks (ANNs and CNNs) in predicting the BDDCS class of 721 substances. The structural parameters and physicochemical properties [Abraham solvation parameters, octanol-water partition (log P) and over the pH range 1–7.5 (log D), number of rotatable bonds, hydrogen bond acceptor numbers, as well as hydrogen bond donor count] are calculated with various software. These compounds were then split into a training set consisting of 602 molecules and a test set of 119 compounds to validate the models. Results The results of this study showed that neural network models using applied parameters of the drug, i.e., log D and Abraham solvation parameters, are able to predict the class of solubility and metabolism in the BDDCS system with good accuracy. Conclusions Neural network models are well equipped to deal with the relations between the structural parameters and physicochemical properties of drugs and BDDCS classes. In addition, log D is a more suitable parameter compared with log P in predicting BDDCS.
      PubDate: 2024-01-01
       
  • Pharmacokinetic Interaction Between Imatinib and Metformin in Rats

    • Free pre-print version: Loading...

      Abstract: Background and Objective Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats. Methods Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software. Results After single-dose co-administration of imatinib and metformin on day 1, the AUC0−24 (area under the plasma concentration-time curve) and Cmax (maximum concentration) of imatinib and the MRT (mean residence time) and Cmax of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC0−24 and Cmax of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05). Conclusion With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.
      PubDate: 2023-12-23
       
  • Novel Techniques and Models for Studying the Role of the Gut Microbiota in
           Drug Metabolism

    • Free pre-print version: Loading...

      Abstract: Abstract The gut microbiota, known as the second human genome, plays a vital role in modulating drug metabolism, significantly impacting therapeutic outcomes and adverse effects. Emerging research has elucidated that the microbiota mediates a range of modifications of drugs, leading to their activation, inactivation, or even toxication. In diverse individuals, variations in the gut microbiota can result in differences in microbe–drug interactions, underscoring the importance of personalized approaches in pharmacotherapy. However, previous studies on drug metabolism in the gut microbiota have been hampered by technical limitations. Nowadays, advances in biotechnological tools, such as microbially derived metabolism screening and microbial gene editing, have provided a deeper insight into the mechanism of drug metabolism by gut microbiota, moving us toward personalized therapeutic interventions. Given this situation, our review summarizes recent advances in the study of gut-microbiota-mediated drug metabolism and showcases techniques and models developed to navigate the challenges posed by the microbial involvement in drug action. Therefore, we not only aim at understanding the complex interaction between the gut microbiota and drugs and outline the development of research techniques and models, but we also summarize the specific applications of new techniques and models in researching gut-microbiota-mediated drug metabolism, with the expectation of providing new insights on how to study drug metabolism by gut microbiota.
      PubDate: 2023-12-21
       
  • Pharmacokinetics of Long-Acting Methylphenidate: Formulation Differences,
           Bioequivalence, Interchangeability

    • Free pre-print version: Loading...

      Abstract: Background and Objective Attention deficit hyperactivity disorder is one of the most common neuropsychiatric conditions in children, and methylphenidate (MPH) is one of the first-line therapies. MPH is available in a variety of extended-release (ER) formulations worldwide, and most formulations are not considered bioequivalent due to differences in pharmacokinetics. It is hypothesized that the current bioequivalence guidelines from the different regulatory bodies may generate inconsistent findings or recommendations when assessing the bioequivalence of ER MPH formulations. This manuscript aims to conduct a comprehensive and narrative critical literature review to analyze pharmacokinetic data pertaining to ER formulations of MPH in order to assess bioequivalence, differences in regulatory guidelines, and additional pharmacokinetic–pharmacodynamic parameters that may help define interchangeability. Methods A literature search was conducted in EMBASE, Medline, and Cochrane Library with no time limits. Study characteristics, non-compartmental pharmacokinetic parameters, and bioequivalence data were extracted for analysis. Results Thirty-three studies were identified with primary pharmacokinetic data after the administration of ER MPH, of which 10 were direct comparative studies (i.e., at least 2 formulations tested within a single setting) and 23 were indirect comparisons (i.e., different experimental settings). Two formulations were consistently reported as bioequivalent across the regulatory bodies using criteria from their guidance documents, although inconsistencies have been observed. However, when additional kinetic criteria (discussed in this manuscript) were imposed, only one study met the more stringent definition of bioequivalence. Various clinical factors also had inconsistent effects on the pharmacokinetics and interchangeability of the different formulations, which were associated with a lack of standardization for assessing covariates across the regulatory agencies. Conclusion Additional pharmacokinetic parameters and consistency in guidelines across the regulatory bodies may improve bioequivalence assessments. Based on our findings, more research is also required to understand whether bioequivalence is an appropriate measure for determining MPH interchangeability. This critical review is suitable for formulation scientists, clinical pharmacologists, and clinicians.
      PubDate: 2023-12-21
       
  • Evaluation of Hydroxychloroquine as a Perpetrator on Cytochrome P450 (CYP)
           3A and CYP2D6 Activity with Microdosed Probe Drugs in Healthy Volunteers

    • Free pre-print version: Loading...

      Abstract: Background and Objective Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers. Methods In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 μg) and the oral microdosed CYP2D6 probe drug yohimbine (50 μg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020). Results The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration–time curve 0–6 h after administration (AUC0–6 h) for yohimbine and the partial AUC2–4 h for midazolam. Under HCQ, yohimbine AUC0–6 h was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC2–4 h was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC2–4 h as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC2–4 h significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026). Conclusion In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.
      PubDate: 2023-12-20
       
  • Comparative Pharmacokinetic Study of Rhubarb Anthraquinones in Normal and
           Nonalcoholic Fatty Liver Disease Rats

    • Free pre-print version: Loading...

      Abstract: Background and Objectives Rhubarb anthraquinones contain five main components, that is, rhein, emodin, aloe-emodin, chrysophanol, and physcion, which demonstrate good therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, research on its pharmacokinetics in NAFLD remains lacking. This study aimed to investigate the pharmacokinetic differences of rhubarb anthraquinones in normal and NAFLD rats. Methods This study developed an NAFLD rat model by high-fat diet feeding for 6 weeks. Normal and NAFLD groups were orally administered different rhubarb anthraquinones doses (37.5, 75, and 150 mg/kg). The concentration of the rhein, emodin, aloe-emodin, chrysophanol, and physcion in plasma was determined by high-performance liquid chromatography–ultraviolet. Results The results revealed significant differences in pharmacokinetic behavior between normal and NAFLD rats. Compared with normal rats, NAFLD rats demonstrated significantly increased maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0 → ∞) of rhubarb anthraquinones (P < 0.05), as well as significantly prolonged time to reach maximum plasma concentration (Tmax), terminal elimination half-life (t1/2), and mean residence time (MRT) of rhubarb anthraquinones (P < 0.05). Conclusions This study indicates significant differences in the pharmacokinetics of rhubarb anthraquinones between the physiological and NAFLD states of rats. Rhubarb anthraquinone demonstrated a longer retention time and slower absorption rate in NAFLD rats and exhibited higher bioavailability and peak concentration. This finding provides important information for guiding the clinical use of rhubarb anthraquinones under pathological conditions.
      PubDate: 2023-12-19
       
  • Development, Physicochemical Characteristics and Pharmacokinetics of a New
           Sustained-Release Bilayer Tablet Formulation of Tramadol with an
           Immediate-Release Component for Twice-Daily Administration

    • Free pre-print version: Loading...

      Abstract: Background and Objective There are some potential concerns about the currently marketed solid oral dosage forms of tramadol, including decreased adherence to immediate-release (IR) formulations due to the high number of doses taken each day and the slow rise in the blood tramadol concentration after administration of sustained-release (SR) formulations, which may not achieve a rapid analgesic effect. To overcome these potential concerns, a twice-daily double-layered tablet formulation of tramadol comprising IR and SR layers was developed. This article reports studies that assessed its physicochemical and pharmacokinetic properties. Methods Dissolution tests of five bilayer tablet formulations (designated tablets A–E) and pharmacokinetic studies of tablets A and B were conducted to investigate the appropriate ratio of the IR/SR layers in the double-layered tablet. Additionally, pharmacokinetic studies of three finished dosage formulations (tablets C–E) were performed in healthy adult males to investigate the effect of food intake on drug absorption. Results Adjusting the excipients and tramadol content in the IR and SR layers of tablets A–E altered their dissolution profiles in a manner that could be predicted based on their compositions. The IR layer was released within 15 min, and the SR layer was slowly released over 10 h. In the pharmacokinetic study, the time to maximum plasma concentration (tmax) of tramadol after administration of tablets A (IR:SR: 20:80 mg) and B (40:60 mg) was shorter than that of a commercially available SR tablet, and the half-life (t1/2) was longer than that of a commercially available IR tablet. For tablets C–E, administration after food did not affect the area under the concentration-time curve (AUC) or maximum drug concentration (Cmax) of tramadol, but the tmax was prolonged by about 1 h compared with administration in fasting conditions. The mean ± standard deviation tmax and t1/2 for tablet D (IR:SR: 35:65 mg) in the fasting condition was 1.09 ± 0.56 h and 7.82 ± 0.85 h, respectively. The respective values in the fed condition were 2.47 ± 1.06 h and 7.12 ± 0.85 h, respectively. Conclusions To address the potential concerns regarding existing formulations of tramadol, a twice-daily, extended-release bilayer formulation of tramadol consisting of an IR and SR layer was developed. Pharmacokinetic studies confirmed that the plasma tramadol concentration increased quickly after administration and was maintained over a long period of time.
      PubDate: 2023-12-08
       
  • Mass Balance and Metabolic Pathways of Eliapixant, a P2X3 Receptor
           Antagonist, in Healthy Male Volunteers

    • Free pre-print version: Loading...

      Abstract: Background Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization. Methods In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [14C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated. Results After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3–99.4%) within 14 days, with 86.3% (84.8–88.1%) excreted via feces and 11.6% (9.5–13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo. Conclusion Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose). Clinical trial registration ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017).
      PubDate: 2023-12-03
       
  • Pharmacokinetic Parameters of Recombinant Human Cyclophilin A in Mice

    • Free pre-print version: Loading...

      Abstract: Background and Objective Cyclophilin A (CypA) is an isomerase that functions as a chaperone, housekeeping protein, and cyclosporine A (CsA) ligand. Secreted CypA is a proinflammatory factor, chemoattractant, immune regulator, and factor of antitumor immunity. Experimental data suggest clinical applications of recombinant human CypA (rhCypA) as a biotherapeutic for cancer immunotherapy, stimulation of tissue regeneration, treatment of brain pathologies, and as a supportive treatment for CsA-based therapies. The objective of this study is to analyze the pharmacokinetics of rhCypA in a mouse model. Methods rhCypA was isotope-labeled with 125I and injected intraperitoneally (i.p.) or subcutaneously (s/c) into female mice as a single dose of 100 μg per mouse, equivalent to the estimated first-in-human dose. Analysis of 125I-rhCypA biodistribution and excretion was performed by direct radiometry of the blood, viscera, and urine of mice 0.5–72 h following its administration. Results rhCypA showed rapid and even tissue–organ distribution, with the highest tropism (fT = 1.56) and accumulation (maximum concentration, Cmax = 137–167 μg/g) in the kidneys, its primary excretory organ. rhCypA showed the lowest tropism to the bone marrow and the brain (fT = 0.07) but the longest retention in these organs [mean retention time (MRT) = 25–28 h]. Conclusion This study identified promising target organs for rhCypA’s potential therapeutic effects. The mode of rhCypA accumulation and retention in organs could be primarily due to the expression of its receptors in them. For the first time, rhCypA was shown to cross the blood–brain barrier and accumulate in the brain. These rhCypA pharmacokinetic data could be extrapolated to humans as preliminary data for possible clinical trials.
      PubDate: 2023-12-01
       
  • Pharmacokinetics of Imatinib Mesylate and Development of Limited Sampling
           Strategies for Estimating the Area under the Concentration–Time Curve of
           Imatinib Mesylate in Palestinian Patients with Chronic Myeloid Leukemia

    • Free pre-print version: Loading...

      Abstract: Background and Objective Imatinib is a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). The area under the concentration–time curve (AUC) is a pharmacokinetic parameter that symbolizes overall exposure to a drug, which is correlated with complete cytogenetic and treatment responses to imatinib, as well as its side effects in patients with CML. The limited sampling strategy (LSS) is considered a sufficiently precise and practical method that can be used to estimate pharmacokinetic parameters such as AUC, without the need for frequent, costly, and inconvenient blood sampling. This study aims to investigate the pharmacokinetic parameters of imatinib, develop and validate a reliable and practical LSS for estimating imatinib AUC0–24, and determine the optimum sampling points for predicting the imatinib AUC after the administration of once-daily imatinib in Palestinian patients with CML. Method Pharmacokinetic profiles, involving six blood samples collected during a 24-h dosing interval, were obtained from 25 Palestinian patients diagnosed with CML who had been receiving imatinib for at least 7 days and had reached a steady-state level. Imatinib AUC0–24 was calculated using the trapezoidal rule, and linear regression analysis was performed to assess the relationship between measured AUC0–24 and concentrations at each sampling time. All developed models were analyzed to determine their effectiveness in predicting AUC0–24 and to identify the optimal sampling time. To evaluate predictive performance, two error indices were employed: the percentage of root mean squared error (% RMSE) and the mean predictive error (% MPE). Bland and Altman plots, along with mountain plots, were utilized to assess the agreement between measured and predicted AUC. Results Among the one-timepoint estimations, predicted AUC0–24 based on concentration of imatinib at the eighth hour after administration (C8-predicted AUC0–24) demonstrated the highest correlation with the measured AUC (r2 = 0.97, % RMSE = 6.3). In two-timepoint estimations, the model consisting of C0 and C8 yielded the highest correlation between predicted and measured imatinib AUC (r2 = 0.993 and % RMSE = 3.0). In three-timepoint estimations, the combination of C0, C1, and C8 provided the most robust multilinear regression for predicting imatinib AUC0–24 (r2 = 0.996, % RMSE = 2.2). This combination also outperformed all other models in predicting AUC. The use of a two-timepoint limited sampling strategy (LSS) for predicting AUC was found to be reliable and practical. While C0/C8 exhibited the highest correlation, the use of C0/C4 could be a more practical and equally accurate choice. Therapeutic drug monitoring of imatinib based on C0 can also be employed in routine clinical practice owing to its reliability and practicality. Conclusion The LSS using one timepoint, especially C0, can effectively predict imatinib AUC. This approach offers practical benefits in optimizing dose regimens and improving adherence. However, for more precise estimation of imatinib AUC, utilizing two- or three-timepoint concentrations is recommended over relying on a single point.
      PubDate: 2023-11-25
      DOI: 10.1007/s13318-023-00868-y
       
  • Ticagrelor Steady-State Trough Concentration in Chinese Patients
           Undergoing Percutaneous Coronary Intervention

    • Free pre-print version: Loading...

      Abstract: Background and Objective Platelets play a pivotal role in thrombotic events associated with acute coronary syndrome (ACS), making oral antiplatelet therapy a cornerstone in antithrombotic strategies. The dosing regimen for the oral antiplatelet drug ticagrelor warrants evaluation to ensure its appropriateness in clinical practice. Therefore, this study aimed to investigate the real-world clinical application of ticagrelor by determining the optimal therapeutic concentration of ticagrelor in Chinese patients undergoing percutaneous coronary intervention (PCI). Methods We enrolled a cohort of 912 patients who underwent PCI with drug-eluting stent implantation for the treatment of ACS. We measured steady-state plasma drug concentrations using high-performance liquid chromatography–tandem mass spectrometry. The therapeutic drug concentration range at steady state was established on the basis of clinical pharmacodynamic indices, with verification of reliability through concentration-effect analysis and receiver operating characteristic curve assessment. Results Analysis of plasma samples from the 912 patients revealed significant variations in the steady-state trough concentration of ticagrelor associated with factors such as gender, age, hypertension, and hyperlipidemia. On the basis of this analysis, the optimal therapeutic range for steady-state trough concentration was determined to be 240.65–335.83 ng/mL. Furthermore, the upper limit values for steady-state concentration were established at 439.97 ng/mL for male patients and 347.06 ng/mL for female patients. Conclusions This study provides robust and reliable insights into the optimal therapeutic steady-state trough concentrations of ticagrelor in Chinese patients with post-percutaneous coronary intervention. These findings have significant implications for guiding the rational use of antiplatelet drugs and facilitating precise drug administration in Chinese patients undergoing percutaneous coronary intervention.
      PubDate: 2023-11-24
      DOI: 10.1007/s13318-023-00867-z
       
  • Pharmacokinetics of 4-Hydroxybenzaldehyde in Normal and Cerebral
           Ischemia–Reperfusion Injury Rats Based on Microdialysis Technique

    • Free pre-print version: Loading...

      Abstract: Aim 4-Hydroxybenzaldehyde (4-HBd) is used for the treatment of headaches, dizziness, and convulsions. The objective of this study was to characterize the pharmacokinetics of 4-HBd in cerebral ischemia-reperfusion injury (CIRI) rats by microdialysis technology with high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography–mass spectrometry (UPLC-MS). Methods Microdialysis was used to collect blood, feces, and urine of normal and CIRI model rats. Pharmacokinetic parameters were determined using HPLC-DAD and 4-HBd metabolites were determined using UPLC-MS. Results After gavage of 4-HBd in normal and middle cerebral artery occlusion/reperfusion (MCAO/R) rats, it was widely distributed to all tissues (heart, liver, spleen, lung, kidney, and brain) in both the equilibrium and elimination phases, and the distribution pattern was basically the same; the highest concentration was found in the brain. The absolute bioavailability of 4-HBd was 5.33%; however, after intragastric administration in normal and MCAO/R rats, fecal and urinary excretion of 4-HBd accounted for 0.02% and 0.01% and for 0.01% and 0.03% of the dosage, respectively. Furthermore, 4-HBd was rapidly metabolized into 4-hydroxybenzoic acid (4-HBA) after administration in both the control and MCAO/R groups. Compared with the control, the peak time of 4-HBd plasma concentration in the MCAO/R rats decreased from 10.67 min to 8.83 min, the area under the concentration-time curve decreased significantly, and the half-life increased from 31.81 min to 78.85 min. Conclusions The rapid absorption and low absolute bioavailability of 4-HBd by gavage in rats are followed by rapid and wide distribution to various tissues and organs, including the brain. The prototype drug is excreted in the feces and urine in low amounts, and it is metabolized to 4-HBA in large amounts in vivo; the pathological state of the MCAO/R model mainly affects its absorption degree and metabolism rate.
      PubDate: 2023-11-24
      DOI: 10.1007/s13318-023-00863-3
       
  • Distribution, Metabolism, and Excretion of Cenobamate in Adult, Fetal,
           Neonatal, and Lactating Rats

    • Free pre-print version: Loading...

      Abstract: Background and Objective Cenobamate is an antiseizure medication (ASM) approved for treatment of focal epilepsy in adults. The objective of this study was to characterize the distribution, metabolism, and excretion of cenobamate in adult and pre- and postnatal rats, including pregnant and lactating females and nursing pups. Methods Distribution, metabolic, and excretion profiles were determined for 14C-labeled and unlabeled cenobamate using liquid scintillation counting, radiochromatography, LCMS, and LCMS/MS after oral or intravenous (IV) administration. Results Distribution of 14C-cenobamate-related material in adult male rats was widespread throughout the body, with nearly 1:1 tissue-to-plasma ratios observed for most tissues, including brain. Cenobamate administered to pregnant females was also transferred across the placental barrier into amniotic fluid and fetal plasma. Following administration to lactating F0 females, cenobamate was detected in breast milk and in plasma of nursing pups. 14C-cenobamate administered to adult male rats as a single oral dose was extensively metabolized with nine metabolites identified in urine and feces, including a principal dihydrodiol metabolite. Cenobamate was the principal drug-related material in rat plasma. Following a single dose of 14C-cenobamate to male and female rats, radioactivity was excreted equally into urine and feces, with mass balance achieved by 48 h postdose. Conclusions Distribution of cenobamate was widespread into many rat tissues, including brain, amniotic fluid, fetal plasma, breast milk, and breastfeeding rat pups. These distribution findings, along with the results of the metabolism and excretion studies, may help inform treatment decisions for patients with epilepsy being treated with cenobamate, including pregnant or nursing mothers.
      PubDate: 2023-11-03
      DOI: 10.1007/s13318-023-00862-4
       
  • Acknowledgement to Referees

    • Free pre-print version: Loading...

      PubDate: 2023-10-30
      DOI: 10.1007/s13318-023-00864-2
       
  • Use of Clearance Concepts to Simulate Impact of Interleukin-6 on Drug
           Elimination Governed by Cytochromes P450 3A4 and Glomerular Filtration
           Rate

    • Free pre-print version: Loading...

      PubDate: 2023-10-04
      DOI: 10.1007/s13318-023-00859-z
       
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
 


Your IP address: 3.235.145.108
 
Home (Search)
API
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-
JournalTOCs
 
 

 A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
The end of the list has been reached or no journals were found for your choice.
Similar Journals
Similar Journals
HOME > Browse the 73 Subjects covered by JournalTOCs  
SubjectTotal Journals
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
 


Your IP address: 3.235.145.108
 
Home (Search)
API
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-