Route Of Elimination Research Articles

Clinical Pharmacokinetics and Safety of Remdesivir in Phase I Participants with Varying Degrees of Renal Impairment.

Remdesivir is a nucleotide analog prodrug approved for the treatment of COVID-19. This study evaluated the pharmacokinetics and safety of remdesivir and its metabolites (GS-704277 and GS-441524) in participants with varying degrees of renal impairment. Results of this phase I study, along with those of a phase III study, contributed to an extension of indication for remdesivir in the USA and Europe for use in patients with COVID-19 with all stages of renal impairment, including those on dialysis, with no dose adjustment. This phase I, open-label, parallel-group study enrolled participants who had mild (n=12), moderate (n = 11), or severe (n = 10) renal impairment or kidney failure (n = 6 with dialysis, n = 4 without dialysis). Healthy matched controls were enrolled as reference. Remdesivir was given as single intravenous doses of 100 mg (mild and moderate renal impairment), 40 mg (severe renal impairment, kidney failure predialysis), and 20 mg (kidney failure postdialysis and without dialysis). Plasma pharmacokinetics of remdesivir were not affected by mild, moderate, or severe renal impairment or kidney failure. Geometric least squares mean ratios ranged from 0.8 to 1.2 for remdesivir area under the plasma concentration-time curve (AUC). GS-704277 AUC was up to 2.8-fold higher and GS-441524 AUC up to 7.9-fold higher in participants with renal impairment. Adverse events and laboratory abnormalities were consistent with the existing safety profile for remdesivir. Observed pharmacokinetics for remdesivir and its metabolites in participants with renal impairment aligned with expected changes based on known routes of elimination. Remdesivir was generally safe and well tolerated in participants with renal impairment, and no new safety concerns were identified. These results, along with those from the phase III study in patients with COVID-19 with severely reduced kidney function, support the use of remdesivir in patients with any degree of renal impairment with no dose adjustments. EudraCT no. 2020-003441-10; 9 July 2020.

Computer Modeling of Bevacizumab Drug Distribution After Intravitreal Injection in Rabbit and Human Eyes.

Age-related macular degeneration (AMD) is a progressive eye disease that causes loss of central vision and has no cure. Wet AMD is the late neovascular form treated with vascular endothelial growth factor (VEGF) inhibitors. VEGF is the critical driver of wet AMD. One common off-label anti-VEGF drug used in AMD treatment is bevacizumab. Experimental efforts have been made to investigate the pharmacokinetic (PK) behavior of bevacizumab in vitreous and aqueous humor. Still, the quantitative effect of elimination routes and drug concentration in the macula are not well understood. In this work, we developed two spatial models representing rabbit and human vitreous to better understand the PK behavior of bevacizumab. This study explores different cases of drug elimination and the effects of injection location on drug concentration profiles. The models are validated by comparing them with experimental data. Our results suggest that anterior elimination is dominant for bevacizumab clearance from rabbit vitreous, whereas both anterior and posterior elimination have similar importance in drug clearance from the human vitreous. Furthermore, results indicate that drug injections closer to the posterior segment of the vitreous help maintain relevant drug concentrations for longer, improving bevacizumab duration of action in the vitreous. The rabbit and human models predict bevacizumab concentration in the vitreous and fovea, enhancing knowledge and understanding of wet AMD treatment.

Characterization of Nonclinical Drug Metabolism and Pharmacokinetic Properties of Phosphorodiamidate Morpholino Oligonucleotides, a Novel Drug Class for Duchenne Muscular Dystrophy.

Eteplirsen, golodirsen, and casimersen are phosphorodiamidate morpholino oligomers (PMOs) that are approved in the United States for the treatment of patients with Duchenne muscular dystrophy (DMD) with mutations in the DMD gene that are amenable to exon 51, 53, and 45 skipping, respectively. Here we report a series of in vivo and in vitro studies characterizing the drug metabolism and pharmacokinetic (DMPK) properties of these three PMOs. Following a single intravenous dose, plasma exposure was consistent for all three PMOs in mouse, rat, and nonhuman primate (NHP), and plasma half-lives were similar for eteplirsen (2.0-4.1 h) and golodirsen (2.1-8.7 h) across species and more variable for casimersen (3.2-18.1 h). Plasma protein binding was low (<40%) for all three PMOs in mouse, rat, NHP, and human and was largely concentration independent. In the mdx mouse model of DMD, following a single intravenous injection, extensive biodistribution was observed in the target skeletal muscle tissues and the kidney for all three PMOs; consistent with the latter finding, the predominant route of elimination was renal. In vitro studies using liver microsomes showed no evidence of hepatic metabolism, and none of the PMOs were identified as inhibitors or inducers of the human cytochrome P450 enzymes or membrane drug transporters tested at clinically relevant concentrations. These findings suggest that key DMPK features are consistent for eteplirsen, golodirsen, and casimersen and provide evidence for the concept of a PMO drug class with potential application to novel exon-skipping drug candidates. SIGNIFICANCE STATEMENT: The PMOs eteplirsen, golodirsen, and casimersen share similar absorption, distribution, metabolism, and excretion and DMPK properties, which provides evidence for the concept of a PMO treatment class. A PMO drug class may support a platform approach to enhance understanding of the pharmacokinetic and pharmacodynamic behavior of these molecules. The grouping of novel agent series into platforms could be beneficial in the development of drug candidates for populations in which traditional clinical trials are not feasible.

Conjugation of Polycationic Peptides Extends the Efficacy Spectrum of β-Lactam Antibiotics.

Antibiotic-resistant enterococci represent a significant global health challenge. Unfortunately, most β-lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β-lactam antibiotics. Remarkably, the β-lactam-peptide conjugates gained an up to 1000-fold increase in antimicrobial activity against vancomycin-susceptible and vancomycin-resistant enterococci. Even against β-lactam-resistant Gram-negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration-dependent activity in contrast to the parent β-lactam antibiotics that exhibited a time-dependent mode of action. In comparison to the parent β-lactams, the conjugates showed altered affinities to the penicillin-binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin-resistant enterococci, treatment with a β-lactam-peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β-lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci.

Metformin (The Miracle Drug) Kinetics in Different Diseases such as Cancer

: Metformin, a miracle drug that was introduced a century ago, could be considered for various aspects of diseases such as diabetes (type 1 and 2), cancer prevention or chemotherapy, metabolic and neurodegenerative disease. It is well known that the frequency of cancer is higher in patients with type 2 diabetes mellitus. This review aims to provide updated information regarding clinical pharmacokinetics and the mechanism of action of Metformin in different diseases such as cancer. Diabetes type 1 is another chronic autoimmune disease detected usually in early childhood due to immune-mediated devastation of insulin-producing pancreatic beta-cells. Because of the lack of effective therapeutic approaches, its prevalence is increasing. Regarding cancer, an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths were reported in 2020 worldwide. By 50-60% bioavailability, the main route of metformin excretion is through urine. Its mechanism of action is based on 1) initiation of adenosine monophosphate-activated kinase, 2) block proinflammatory paths in perivascular adipose tissue, 3) decrease in monocyte-to-macrophage differentiation in vascular tissues, and 4) improvement in endothelial function. Metformin induces adenosine monophosphate-activated protein kinase signaling and suppresses gluconeogenesis. Antitumor properties of Metformin include a decrease in reactive oxygen species generation and inducing autophagy. In addition to glucose-lowering effects, Metformin has moderate anti-inflammatory and antioxidative effects. It could improve lipid profile and reduce overweight individuals' body mass and arterial blood pressure. In type 1 diabetes, Metformin reduces the requirement for daily insulin and improves glycemia. Its long-term use decreases cardiovascular events. In addition to inhibiting the synthesis of lipids via a reduction in oxidative stress, Metformin inhibits inflammation and increases energy metabolism. Finally, by reducing micro- and macro-vascular consequences, mortality-related diabetes and cancer decline by metformin administration. Therefore, in addition to diabetes, Metformin could reduce the proliferation of cancer cells and the possibility of malignancies in different types of cancer.

Pharmacokinetics and ADME Profiling of Tanimilast Following an Intravenous 14C-Microtracer co-administered with an Inhaled Dose in Healthy Male Individuals.

Tanimilast is an inhaled phosphodiesterase-4 inhibitor currently in phase 3 clinical development for treating chronic obstructive pulmonary disease (COPD) and asthma. This trial aimed to characterize the pharmacokinetics, mass balance, and metabolite profiling of tanimilast. Eight healthy male volunteers received a single dose of non-radiolabeled tanimilast via powder inhaler (NEXThaler® (3200μg)), followed by a concomitant intravenous (IV) infusion of a microtracer ([14C]-tanimilast: 18.5μg and 500nCi). Plasma, whole blood, urine, and feces samples were collected up to 240 hours post-dose to quantify non-radiolabeled tanimilast, [14C]-tanimilast, and total-[14C]. The inhaled absolute bioavailability of tanimilast was found to be approximately 50%. Following IV administration of [14C]-tanimilast, plasma clearance was 22 L/h, the steady-state volume of distribution was 201 L, and the half-life was shorter compared to inhaled administration (14 vs. 39 hours, respectively), suggesting that plasma elimination is limited by the absorption rate from the lungs. 79% (71% in feces; 8% in urine) of the IV dose was recovered in excreta as total-[14C]. [14C]-tanimilast was the major radioactive compound in plasma, while no recovery was observed in urine and only 0.3% was recovered in feces, indicating predominant elimination through metabolic route. Importantly, as far as no metabolites accounting for more than 10% of the circulating drug-related exposure in plasma or the administered dose in excreta were detected, no further qualification is required according to regulatory guidelines. This study design successfully characterized the absorption, distribution, and elimination of tanimilast, providing key pharmacokinetic parameters to support its clinical development and regulatory application. Significance Statement This trial investigates PK and ADME profile of tanimilast, an inhaled PDE4 inhibitor for COPD and asthma. Eight male volunteers received a dose of non-radiolabeled tanimilast via NEXThaler® and a microtracer IV dose. Results show pivotal PK results for the characterization of tanimilast, excretion route and quantification of significant metabolites, facilitating streamlined clinical development and regulatory approval.

A First-Passage Model of Intravitreal Drug Delivery and Residence Time-Influence of Ocular Geometry, Individual Variability, and Injection Location.

Standard of care for various retinal diseases involves recurrent intravitreal injections. This motivates mathematical modeling efforts to identify influential factors for ocular drug residence time, aiming to minimize administration frequency. We sought to describe the vitreal diffusion of therapeutics in nonclinical species frequently used during drug development assessments. In human eyes, we investigated the impact of variability in vitreous cavity size and eccentricity, and in injection location, on drug disposition. Using a first-passage time approach, we modeled the transport-controlled distribution of two standard therapeutic protein formats (Fab and IgG) and elimination through anterior and posterior pathways. Anatomical three-dimensional geometries of mouse, rat, rabbit, cynomolgus monkey, and human eyes were constructed using ocular images and biometry datasets. A scaling relationship was derived for comparison with experimental ocular half-lives. Model simulations revealed a dependence of residence time on ocular size and injection location. Delivery to the posterior vitreous resulted in increased vitreal half-life and retinal permeation. Interindividual variability in human eyes had a significant influence on residence time (half-life range of 5-7days), showing a strong correlation to axial length and vitreal volume. Anterior exit was the predominant route of drug elimination. Contribution of the posterior pathway displayed a 3% difference between protein formats but varied between species (10%-30%). The modeling results suggest that experimental variability in ocular half-life is partially attributed to anatomical differences and injection site location. Simulations further suggest a potential role of the posterior pathway permeability in determining species differences in ocular pharmacokinetics.

Modeling chemical bioaccumulation in snakes, part 2: Model testing and high-throughput simulation

In part 2 of the physiologically based kinetic (PBK) model for snakes, using default and generic input values, the simulation outcomes showed that chemicals with moderate lipophilicity, low volatility, and low biotransformability exhibited a high potential for biotransfer in the snake’s skin. Furthermore, the inclusion or exclusion of the skin compartment in the PBK model had a substantial impact on the fate, transport, and distribution of these chemicals within the snake’s body. In comparison to the elimination routes via blood transport and volatilization, the shedding of skin and growth processes did not contribute substantially to the overall kinetics of chemical elimination from the skin for most chemicals. The proposed model has demonstrated a consistent alignment with the observed patterns of chemical distribution, as supported by certain experimental data. Furthermore, it has the potential to provide an explanation for and enhance the understanding of the discrepancies found in other field observations. The modeling exercise clearly illustrated the significant role of the skin compartment in the biotransfer of chemicals within the snake’s body and highlighted the importance of including the snake’s physiological features into the PBK model. To further enhance the model’s performance and accuracy, additional research focused on obtaining specific physiological data pertaining to snakes would be beneficial.

Metabolism and disposition of zamicastat in rats

The metabolism and disposition of zamicastat, a reversible dopamine β-hydroxylase (DβH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [14C]-zamicastat. Zamicastat was rapidly absorbed and widely distributed to peripheral tissues, with total radioactivity almost completely recovered 168 h post-dose. Its main route of excretion was via faeces, whilst urine and expired air had minor roles. Maximum plasma concentration of zamicastat-related radioactivity occurred in the first hours, remaining quantifiable up to 144 h. The unchanged zamicastat plasma peak was 2 h post-dose and declined to low levels over 24 h. Zamicastat metabolism occurs largely during the first 8 h with only one metabolite identified in the latest time-point (96 h), the isocyanic acid/thiocyanic acid (tautomeric forms). Zamicastat metabolic pathway involved multiple reactions comprising desulphurisation, oxidative desulphurisation, N-debenzylation followed by further oxidation or N-acetylation, and the unexpected multistep metabolic pathway leading to isocyanic acid/thiocyanic acid.

Pharmacokinetics, disposition, and biotransformation of the cardiac myosin inhibitor aficamten in humans.

Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median tmax of 2.0 h postdose. The median t1/2 of aficamten was 99.6 h with similar t1/2 observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK-3834282) and M1b (CK-3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median tmax of 5 h. The other major plasma metabolite was M5 (an oxygen-linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a tmax of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.

Preclinical evaluation and first-in-human study of [18F]AlF-FAP-NUR for PET imaging cancer-associated fibroblasts

BackgroundFibroblast activation protein (FAP) has gained attention as a promising molecular target with potential utility for cancer diagnosis and therapy. [68Ga]Ga-labeled FAP-targeting peptides have been successfully applied to positron emission tomography (PET) imaging of various tumor types. To meet the applicable demand for peptide-based FAP tracers with high patient throughput, we herein report the radiosynthesis, preclinical evaluation, and the first-in-human imaging of a novel [18F]F-labeled FAP-targeting peptide.Results[18F]AlF-FAP-NUR was automatedly prepared within 45 min with a non-decay corrected radiochemical yield of 18.73 ± 4.25% (n = 3). Compared to [68Ga]Ga-FAP-2286, the [18F]F-labeled peptide demonstrated more rapid, higher levels of cellular uptake and internalization, and lower levels of cellular efflux in HT1080-FAP cells. Micro-PET imaging and biodistribution studies conducted on xenograft mice models revealed a similar distribution pattern between the two tracers. However, [18F]AlF-FAP-NUR demonstrated significantly higher tumor-specific uptake resulting in improved Tumor-Background Ratios (TBRs). In the patients, a significant accumulation of [18F]AlF-FAP-NUR was found in the primary tumor. High uptake of the tracer within the bladder indicated that its major route of excretion was through urine.ConclusionsBased on the physical imaging properties and longer half-life of [18F]F, [18F]AlF-FAP-NUR exhibited promising characteristics such as enhanced tumor-specific accumulation and elevated TBRs, which made it a viable candidate for further clinical investigation.Trial registrationwww.Chictr.org.cn, ChiCTR2300076976 Retrospectively registered 25 October 2023. at, URL: https://www.chictr.org.cn/showproj.html?proj=206753.

Absorption, distribution, metabolism, and excretion of tirzepatide in humans, rats, and monkeys

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist used for treatment of type 2 diabetes (T2D) in adults and was recently approved for treatment of obesity. To determine the absorption, distribution, metabolism, and excretion (ADME) of tirzepatide, [14C]-radiolabeled tirzepatide was investigated in both humans and preclinical species. [14C]-Tirzepatide was prepared by incorporating four 14C's in the linker region between the amino acid backbone and the di-acid moiety. Healthy male participants received a single subcutaneous dose of approximately 2.9 mg tirzepatide containing approximately 100 μCi of [14C]-tirzepatide. Preclinical studies were conducted in male Sprague Dawley and Long Evans rats administered a single dose of 3 mg kg-1 (133 µCi/kg) of [14C]-tirzepatide, and male cynomolgus monkeys administered a single dose of 0.5 mg kg-1 (20 µCi/kg) of [14C]-tirzepatide. Following a single SC dose of [14C]-tirzepatide in humans, the majority of the excreted dose was recovered within 480 h. Renal excretion was identified as a principal route of elimination in all species with approximately 66 % of the administered radioactivity recovered in urine, while approximately 33 % was eliminated in feces in humans. Metabolite analysis of tirzepatide revealed the parent drug was the major circulating component in human, rat, and monkey plasma. Metabolites identified in human plasma were similar to circulating metabolites found in rats and monkeys with no circulating metabolites representing >10 % of the total radioactive drug-related exposure. Intact tirzepatide was not observed in urine or feces in any species. Tirzepatide was primarily metabolized via proteolytic cleavage of the amino acid backbone, β-oxidation of the C20 diacid moiety, and amide hydrolysis.ClinicalTrials.gov identifier: NCT 04,311,424

113mIn]In-PSMA: high potential agent for SPECT imaging of prostate cancer

Abstract The prevalence rate of prostate cancer is very high and unfortunately causes many deaths worldwide. This study aimed to prepare [113mIn]In-PSMA as a novel agent for single photon emission computed tomography (SPECT) imaging of prostate cancer. 113mIn was eluted from an in-house made 113Sn/113mIn generator in chloride form, and its radionuclide, chemical and radiochemical purities was studied. [113mIn]In-PSMA was prepared with radiochemical purity (RCP) &gt; 99 % under optimal labeling conditions. The biodistribution of the labeled compound was studied in normal rats, showed the major activity in the urine and kidneys as the main excretion route from the body. Considerable uptake was observed in the prostate and salivary glands as the PSMA-expressing organs. These data are in complete agreement with the other published data on PSMA-labeled compounds both in animals and humans. The results demonstrated [113mIn]In-PSMA can be considered as a good option for SPECT imaging of prostate cancer.

Torsemide in Edema Associated with Chronic Kidney Disease.

Torsemide is a loop diuretic used to manage edema associated with chronic kidney disease (CKD) and acute kidney injury (AKI). It acts by inhibiting sodium and chloride ions reabsorption in the ascending limb of the loop of Henle, thereby increasing urine output and reducing fluid accumulation. Compared to other diuretics, torsemide has an extended duration of action, higher bioavailability, and its elimination route is primarily through the hepatic route, making it effective in patients with CKD and AKI. Clinical studies indicate that torsemide can improve symptoms of fluid overload and potentially enhance renal function.

Viral shedding and environmental dispersion of two clade 2.3.4.4b H5 high pathogenicity avian influenza viruses in experimentally infected mule ducks: implications for environmental sampling

High pathogenicity avian influenza viruses (HPAIVs) have caused major epizootics in recent years, with devastating consequences for poultry and wildlife worldwide. Domestic and wild ducks can be highly susceptible to HPAIVs, and infection leads to efficient viral replication and massive shedding (i.e., high titres for an extended time), contributing to widespread viral dissemination. Importantly, ducks are known to shed high amounts of virus in the earliest phase of infection, but the dynamics and impact of environmental contamination on the epidemiology of HPAIV outbreaks are poorly understood. In this study, we monitored mule ducks experimentally infected with two H5N8 clade 2.3.4.4b goose/Guangdong HPAIVs sampled in France in 2016–2017 and 2020–2021 epizootics. We investigated viral shedding dynamics in the oropharynx, cloaca, conjunctiva, and feathers; bird-to-bird viral transmission; and the role of the environment in viral spread and as a source of samples for early detection and surveillance. Our findings showed that viral shedding started before the onset of clinical signs, i.e., as early as 1 day post-inoculation (dpi) or post-contact exposure, peaked at 4 dpi, and lasted for up to 14 dpi. The detection of viral RNA in aerosols, dust, and water samples mirrored viral shedding dynamics, and viral isolation from these environmental samples was successful throughout the experiment. Our results confirm that mule ducks can shed high HPAIV titres through the four excretion routes tested (oropharyngeal, cloacal, conjunctival, and feather) while being asymptomatic and that environmental sampling could be a non-invasive tool for early viral RNA detection in HPAIV-infected farms.

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 hours, 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 (CYP) 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 pharmacokinetics 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, such as clearance, volume of distribution, and bioavailability, allowing for a more comprehensive understanding of drug disposition.

Correlation between Molecular Docking and the Stabilizing Interaction of HOMO-LUMO: Spirostans in CHK1 and CHK2, an In Silico Cancer Approach.

Checkpoint kinases 1 and 2 (CHK1 and CHK2) are enzymes that are involved in the control of DNA damage. At the present time, these enzymes are some of the most important targets in the fight against cancer since their inhibition produces cytotoxic effects in carcinogenic cells. This paper proposes the use of spirostans (Sp), natural compounds, as possible inhibitors of the enzymes CHK1 and CHK2 from an in silico analysis of a database of 155 molecules (S5). Bioinformatics studies of molecular docking were able to discriminate between 13 possible CHK1 inhibitors, 13 CHK2 inhibitors and 1 dual inhibitor for both enzymes. The administration, distribution, metabolism, excretion and toxicity (ADMETx) studies allowed a prediction of the distribution and metabolism of the potential inhibitors in the body, as well as determining the excretion routes and the appropriate administration route. The best inhibition candidates were discriminated by comparing the enzyme-substrate interactions from 2D diagrams and molecular docking. Specific inhibition candidates were obtained, in addition to studying the dual inhibitor candidate and observing their stability in dynamic molecular studies. In addition, Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) interactions were analyzed to study the stability of interactions between the selected enzymes and spirostans resulting in the predominant gaps from HOMOCHKs to LUMOSp (Highest Occupied Molecular Orbital of CHKs-Lowest Unoccupied Molecular Orbital of spirostan). In brief, this study presents the selection inhibitors of CHK1 and CHK2 as a potential treatment for cancer using a combination of molecular docking and dynamics, ADMETx predictons, and HOMO-LUMO calculation for selection.

Novel drug design and repurposing: An opportunity to improve translational research in cardiovascular diseases?

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.

Catalytic Hydrolysis-Oxidation of Halogenated Methanes over Phase- and Defect-Engineered CePO4: Halogenated Byproduct-Free and Stable Elimination.

Catalytic elimination of halogenated volatile organic compound (HVOC) emissions was still a huge challenge through conventional catalytic combustion technology, such as the formation of halogenated byproducts and the destruction of the catalyst structure; hence, more efficient catalysts or a new route was eagerly desired. In this work, crystal phase- and defect-engineered CePO4 was rationally designed and presented abundant acid sites, moderate redox ability, and superior thermal/chemical stability; the halogenated byproduct-free and stable elimination of HVOCs was achieved especially in the presence of H2O. Hexagonal and defective CePO4 with more structural H2O and Brønsted/Lewis acid sites was more reactive and durable compared with monoclinic CePO4. Based on the phase and defect engineering of CePO4, in situ diffuse reflectance infrared Fourier transform spectra (DRIFTS), and kinetic isotope effect experiments, a hydrolysis-oxidation pathway characterized by the direct involvement of H2O was proposed. Initiatively, an external electric field (5 mA) significantly accelerated the elimination of HVOCs and even 90% conversion of dichloromethane could be obtained at 170 °C over hexagonal CePO4. The structure-performance-dependent relationships of the engineered CePO4 contributed to the rational design of efficient catalysts for HVOC elimination, and this pioneering work on external electric field-assisted catalytic hydrolysis-oxidation established an innovative HVOC elimination route.

Metabolism and Excretion of [14C]Mobocertinib, a Selective Covalent Inhibitor of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations, in Healthy Male Subjects.

Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib-related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for six individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other cytochrome P450s, and renal excretion of unchanged mobocertinib. SIGNIFICANCE STATEMENT: This article describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.