RESUMEN
Dose-scale pharmacodynamic bioequivalence is recommended for evaluating the consistency of generic and innovator formulations of certain locally acting drugs, such as orlistat. This study aimed to investigate the standard methodology for sample size determination and the impact of study design on dose-scale pharmacodynamic bioequivalence using orlistat as the model drug. A population pharmacodynamic model of orlistat was developed using NONMEM 7.5.1 and utilized for subsequent simulations. Three different study designs were evaluated across various predefined relative bioavailability ratios of test/reference (T/R) formulations. These designs included Study Design 1 (2×1 crossover with T1 60 mg, R1 60 mg, and R2 120 mg), Study Design 2 (2×1 crossover with T2 120 mg, R1 60 mg, and R2 120 mg), and Study Design 3 (2×2 crossover with T1 60 mg, T2 120 mg, R1 60 mg, and R2 120 mg). Sample sizes were determined using a stochastic simulation and estimation approach. Under the same T/R ratio and power, Study Design 3 required the minimum sample size for bioequivalence, followed by Study Design 1, while Study Design 2 performed the worst. For Study Designs 1 and 3, a larger sample size was needed on the T/R ratio < 1.0 side for the same power compared to that on the T/R ratio > 1.0 side. The opposite asymmetry was observed for Study Design 2. We demonstrated that Study Design 3 is most effective for reducing the sample size for orlistat bioequivalence studies, and the impact of T/R ratio on sample size shows asymmetry.
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Estudios Cruzados , Orlistat , Equivalencia Terapéutica , Orlistat/farmacocinética , Orlistat/administración & dosificación , Humanos , Tamaño de la Muestra , Proyectos de Investigación , Disponibilidad Biológica , Modelos Biológicos , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/administración & dosificación , Lactonas/farmacocinética , Lactonas/administración & dosificación , Simulación por Computador , Relación Dosis-Respuesta a DrogaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal remedy Atractylodes macrocephala Koidz is renowned for its purported gastrointestinal regulatory properties and immune-enhancing capabilities. Atractylenolide III (ATL III), a prominent bioactive compound in Atractylodes macrocephala Koidz, has demonstrated significant pharmacological activities. However, its impact on neuroinflammation, oxidative stress, and therapeutic potential concerning Alzheimer's disease (AD) remain inadequately investigated. AIM OF THE STUDY: This study aims to assess the plasma pharmacokinetics of ATL III in Sprague-Dawley (SD) rats and elucidate its neuropharmacological effects on AD via the PI3K/AKT/GSK3ß pathway. Through this research, we endeavor to furnish experimental substantiation for the advancement of novel therapeutics centered on ATL III. MATERIALS AND METHODS: The pharmacokinetic profile of ATL III in SD rat plasma was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). AD models were induced in SD rats through bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ). ATL III was administered at doses of 0.6 mg/kg, 1.2 mg/kg, and 2.4 mg/kg, while donepezil (1 mg/kg) served as control. Cognitive function assessments were conducted employing behavioral tests including the Morris Water Maze and Novel Object Recognition. Neuronal pathology and histological changes were evaluated through Nissl staining and Hematoxylin-Eosin (HE) staining, respectively. Oxidative stress levels were determined by quantifying malondialdehyde (MDA) content and total superoxide dismutase (T-SOD) activity. Molecular docking analysis was employed to explore the direct binding between ATL III and its relevant targets, followed by validation using Western blot (WB) experiments to assess the expression of p-Tau, PI3K, AKT, GSK3ß, and their phosphorylated forms. RESULTS: Within the concentration range of 5-500 ng/mL, ATL III demonstrated exceptional linearity (R2 = 0.9991), with a quantification limit of 5 ng/mL. In male SD rats, ATL III exhibited a Tmax of 45 min, a t1/2 of 172.1 min, a Cmax of 1211 ng/L, and an AUC(0-t) of 156031 ng/L*min. Treatment with ATL III significantly attenuated Tau hyperphosphorylation in intracerebroventricular-streptozotocin (ICV-STZ) rats. Furthermore, ATL III administration mitigated neuroinflammation and oxidative stress, as evidenced by reduced Nissl body loss, alleviated histological alterations, decreased MDA content, and enhanced T-SOD activity. Molecular docking analyses revealed strong binding affinity between ATL III and the target genes PI3K, AKT, and GSK3ß. Experimental validation corroborated that ATL III stimulated the phosphorylation of PI3K and AKT while reducing the phosphorylation of GSK3ß. CONCLUSIONS: Our results indicate that ATL III can mitigate Tau protein phosphorylation through modulation of the PI3K/AKT/GSK3ß pathway. This attenuation consequently ameliorates neuroinflammation and oxidative stress, leading to enhanced learning and memory abilities in ICV-STZ rats.
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Disfunción Cognitiva , Glucógeno Sintasa Quinasa 3 beta , Lactonas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Sesquiterpenos , Estreptozocina , Animales , Masculino , Ratas , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Lactonas/farmacología , Lactonas/farmacocinética , Lactonas/administración & dosificación , Aprendizaje por Laberinto/efectos de los fármacos , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Sesquiterpenos/farmacología , Sesquiterpenos/farmacocinética , Sesquiterpenos/administración & dosificación , Transducción de Señal/efectos de los fármacosRESUMEN
Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open-label, parallel-group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child-Pugh B, n = 8) and severe (Child-Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m2. The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration-time curve) in participants with moderate and severe HI was â¼40% and â¼60% higher, respectively, compared with healthy matched controls based on Child-Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m2 should be reduced by â¼30%, to 170 mg/m2, for patients with moderate or severe HI.
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Antineoplásicos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antineoplásicos/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Triazoles/farmacocinética , Triazoles/administración & dosificación , Hepatopatías/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Lactonas/farmacocinética , Lactonas/administración & dosificación , Adulto , Área Bajo la Curva , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas , PirrolesRESUMEN
Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0-24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0-24 h (1.5 - 3.2-fold) and Cmax (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0-24 h reduced to 47 - 67%, Cmax to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC0-24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.
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Cinarizina , Lípidos , Cinarizina/química , Cinarizina/farmacocinética , Cinarizina/administración & dosificación , Animales , Masculino , Lípidos/química , Solubilidad , Lactonas/química , Lactonas/farmacocinética , Lactonas/administración & dosificación , Ratas Wistar , Orlistat/administración & dosificación , Orlistat/farmacocinética , Absorción Intestinal , Ratas , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Lipasa/antagonistas & inhibidores , Polivinilos/química , Precipitación Química , Tensoactivos/química , Química Farmacéutica/métodosRESUMEN
Diterpene lactones have been identified as active compounds in several medicinal plants, including Andrographis paniculata (Burm. f.) Nees, which is a medicinal plant that has been used for centuries across the world. Andrographolide is the major diterpene from A. paniculata and the main bioactive constituent of this species. The effectiveness of diterpenes can be affected by factors that limit their oral bioavailability, such as their poor water solubility, slow dissolution rates, low gastrointestinal absorption, high chemical and metabolic instability, and rapid excretion. In this context, the purpose of the present review is to compile and compare literature data on the bioavailability of diterpene lactones from A. paniculata after oral administration in medicinal plant extracts or in their free forms and to highlight strategies that have been used to improve their oral bioavailability. Considering that medicinal plant extracts are commonly used as dried powder that is reconstituted in water before oral administration, novel pharmaceutical formulation strategies that are used to overcome difficulties with diterpene solubility are also compiled in this review. The use of self-microemulsifying drug delivery systems is a good strategy to enhance the dissolution and consequently the bioavailability of andrographolide after oral administration of A. paniculata extract formulations. On the other hand, herbosome technology, pH-sensitive nanoparticles, nanosuspensions, nanoemulsions, nanocrystal suspensions, nanocrystal-based solid dispersions, and solid dispersion systems are useful to formulate andrographolide in its free form and increase its oral bioavailability. The use of a suitable andrographolide delivery system is essential to achieve its therapeutic potential.
Asunto(s)
Andrographis paniculata , Diterpenos/farmacocinética , Lactonas/farmacocinética , Extractos Vegetales/farmacocinética , Administración Oral , Disponibilidad Biológica , Diterpenos/administración & dosificación , Composición de Medicamentos , Humanos , Lactonas/administración & dosificación , Fitoterapia , Extractos Vegetales/administración & dosificación , Plantas MedicinalesRESUMEN
Natural dibenzo-α-pyrones (DAPs) can be viewed from two opposite angles. From one angle, the gastrointestinal metabolites urolithins are regarded as beneficial, while from the other, the emerging mycotoxin alternariol and related fungal metabolites are evaluated critically with regards to potential hazardous effects. Thus, the important question is: can the structural characteristics of DAP subgroups be held responsible for distinct bioactivity patterns? If not, certain toxicological and/or pharmacological aspects of natural DAPs might yet await elucidation. Thus, this review focuses on comparing published data on the two groups of natural DAPs regarding both adverse and beneficial effects on human health. Literature on genotoxic, estrogenic, endocrine-disruptive effects, as well as on the induction of the cellular anti-oxidative defense system, anti-inflammatory properties, the inhibition of kinases, the activation of mitophagy and the induction of autophagy, is gathered and critically reviewed. Indeed, comparing published data suggests similar bioactivity profiles of alternariol and urolithin A. Thus, the current stratification into hazardous Alternaria toxins and healthy urolithins seems debatable. An extrapolation of bioactivities to the other DAP sub-class could serve as a promising base for further research. Conclusively, urolithins should be further evaluated toward high-dose toxicity, while alternariol derivatives could be promising chemicals for the development of therapeutics.
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Antiinflamatorios no Esteroideos/farmacología , Cumarinas/metabolismo , Cumarinas/farmacología , Cumarinas/toxicidad , Lactonas/farmacocinética , Alternaria/metabolismo , Animales , Cumarinas/farmacocinética , Estrógenos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Humanos , Lactonas/metabolismo , Mitofagia/efectos de los fármacos , Pruebas de Mutagenicidad , Micotoxinas/farmacocinéticaRESUMEN
Afidopyropen is an insecticide that acts as a transient receptor potential vanilloid subtype (TRPV) channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including chronic toxicity and carcinogenicity in rats and mice. The current study evaluates the toxicokinetic properties of afidopyropen and its plasma metabolites in rats at dose levels where the pharmacokinetics (PK) are linear and nonlinear in an attempt to identify a point of inflection. Based on the results of this study and depending on the analysis method used, the kinetically derived maximum dose (KMD) is estimated to be between 2.5 and 12.5 mg/kg bw/d with linearity observed at doses below 2.5 mg/kg bw/d. A defined point of inflection could not be determined. These data demonstrate that consideration of PK is critical for improving the dose-selection in toxicity studies as well as to enhance human relevance of the interpretation of animal toxicity studies. The study also demonstrates the technical difficulty in obtaining a defined point of inflection from in vivo PK data.
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Compuestos Heterocíclicos de 4 o más Anillos/toxicidad , Insecticidas/toxicidad , Lactonas/toxicidad , Pruebas de Toxicidad Subaguda/métodos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Insecticidas/administración & dosificación , Insecticidas/farmacocinética , Lactonas/administración & dosificación , Lactonas/farmacocinética , Masculino , Modelos Animales , Ratas , Organismos Libres de Patógenos Específicos , Pruebas de Toxicidad , ToxicocinéticaRESUMEN
Different technologies to prepare long term pesticide forms include polymer coating, preparing composites and encapsulating pesticides in nanoparticles. A simple and low-cost method was proposed to obtain slow-release formulations by co-extrusion of a pesticide with a biodegradable polymer at a temperature above the melting points of both components. A herbicide metribuzin and low-melting polyester poly-ε-caprolactone were chosen for this work. Formulations containing 10%, 20%, and 40% herbicide were prepared. During 7 days of their exposition in water, it was released from 81% to 96% of initially loaded metribuzin; the highest release was detected for 40%-loaded forms. Biodegradation of the constructs and pesticide release were further studied in the model soil. Degradation rates of the specimens increased with an increase in pesticide content, from 9% to 20% over 14 weeks for the 10%/20%-loaded and the 40%-loaded specimens, respectively. The release of metribuzin reached, respectively, 37-38% and 55%. The herbicide content in soil was lower due to its partial degradation in soil; it reached 23-25% and 33%, respectively, from initially loaded into the polymer matrix. Release kinetics of metribuzin in water as in soil best fitted the First-order model. The used approach is promising for obtaining long-term release formulations for soil applications.
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Caproatos/química , Herbicidas/química , Lactonas/química , Poliésteres/química , Contaminantes del Suelo/química , Triazinas/química , Biodegradación Ambiental , Caproatos/análisis , Caproatos/farmacocinética , Preparaciones de Acción Retardada , Composición de Medicamentos , Herbicidas/análisis , Herbicidas/farmacocinética , Cinética , Lactonas/análisis , Lactonas/farmacocinética , Poliésteres/análisis , Poliésteres/farmacocinética , Suelo/química , Contaminantes del Suelo/análisis , Contaminantes del Suelo/farmacocinética , Triazinas/análisis , Triazinas/farmacocinéticaRESUMEN
One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.
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Presentación de Antígeno/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunidad Celular/efectos de los fármacos , Inmunoterapia , Lactonas/farmacología , Neoplasias Experimentales/terapia , Sesquiterpenos/farmacología , Animales , Antígenos de Neoplasias/genética , Células HCT116 , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacocinética , Inmunidad Celular/genética , Lactonas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Sesquiterpenos/farmacocinéticaRESUMEN
Ketolide antibiotics are known to cause hepatic injury. Nafithromycin, a novel lactone ketolide was therefore assessed for hepatic safety through range of preclinical in vitro (metabolic stability, CYP inhibition/induction assays) and in vivo (mass balance and repeat dose toxicity) studies. Repeat-dose toxicity studies in rat and dog revealed that nafithromycin did not cause adverse hematological, biochemical and histopathological changes suggestive of systemic or hepatobiliary safety concern at exposures 3-8 fold higher than targeted therapeutic exposures. The only histological finding noticed was reversible phospholipidosis, mainly in lung and lymphoid organs but not in liver, indicating lower nafithromycin accumulation in liver. This observation was corroborated with lack of biologically relevant elevation of hepatic enzymes linked to hepatic injury. In vitro studies showed that nafithromycin undergoes moderate CYP3A mediated metabolism. Unlike other ketolides, nafithromycin and its metabolites showed weak inhibition of CYP3A isoform and lacked CYP2D6 inhibition. Due to hydrophilic nature, nafithromycin in addition to hepatic clearance is also eliminated unchanged by kidneys in significant amount, thereby minimizing hepatic burden. Based on the scientifically integrated evidences such as moderate metabolism, weak CYP inhibition, lack of CYP induction, minimal accumulation in liver, nafithromycin showed promising hepatic safety profile suitable for its intended community-based usage.
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Antibacterianos/toxicidad , Cetólidos/toxicidad , Lactonas/toxicidad , Hígado/efectos de los fármacos , Animales , Antibacterianos/farmacocinética , Línea Celular , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Cetólidos/farmacocinética , Lactonas/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
BACKGROUND: As parasite resistance to the main artemisinin drugs has emerged in Southern Asia, the traditional herb Artemisia annua L. (AAL) from which artemisinin (QHS) isolated was found to overcome resistance to QHS. However the component and metabolite profiles of AAL remain unclear. OBJECTIVE: In this study, component profiling of marker compounds in AAL (amorphane sesquiterpene lactones and flavonoids) was performed and their subsequent metabolism was investigated in rats. METHODS: For efficient component classification and structural characterization, an improved liquid chromatography- tandem high-resolution mass spectrometry (HRMS)-based analytical strategy was applied, i.e., background subtraction (BS) followed by ring-double-bond (RDB) filter in tandem with repeated BS processing. Structures of detected components/metabolites were characterized based on integrated information including their HRMSn patterns, RDB values, the established component/metabolite network, the biosynthesis pathways of AAL, and/or NMR data. RESULTS: A total of 38 amorphane sesquiterpene lactones and 35 flavonoids were found in AAL as prototype compounds, among which 26 components were previously undescribed. Major compounds were identified by comparing them with reference standards. Among 73 AAL prototypes administered, 38 were absorbed in the circulation as the prototype. Moreover, 20 metabolites of amorphane sesquiterpene lactones and 10 metabolites of flavonoids were detected in rats. The major metabolic pathways included oxidation, methylation, glucuronidation and sulfation. CONCLUSION: The component and metabolite network were established for marker components in AAL, which will be valuable to understand the synergistic antimalarial potency of QHS in A. annua L. The analytical strategy can also be applied to other herbal medicines.
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Artemisia annua/química , Cromatografía de Gases y Espectrometría de Masas/métodos , Sesquiterpenos/farmacocinética , Animales , Artemisininas/aislamiento & purificación , Artemisininas/metabolismo , Artemisininas/farmacocinética , Lactonas/aislamiento & purificación , Lactonas/metabolismo , Lactonas/farmacocinética , Masculino , Ratas , Ratas Wistar , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/metabolismoRESUMEN
In an attempt to search for selective inhibitors against the SARS-CoV-2 which caused devastating of lives and livelihoods across the globe, 415 natural metabolites isolated from several plants, fungi and bacteria, belonging to different classes, were investigated. The drug metabolism and safety profiles were computed in silico and the results showed seven compounds namely fusaric acid, jasmonic acid, jasmonic acid methyl ester, putaminoxin, putaminoxin B and D, and stagonolide K were predicted to having considerable absorption, metabolism, distribution and excretion parameters (ADME) and safety indices. Molecular docking against the receptor binding domain (RBD) of spike glycoprotein (S1) and the main protease (Mpro) exposed the compounds having better binding affinity to main protease as compared to the S1 receptor binding domain. The docking results were compared to an antiviral drug penciclovir reportedly of clinical significance in treating the SARS-CoV-2 infected patients. The results demonstrated the test compounds jasmonic acid, putaminoxins B and D bound to the HIS-CYS catalytic dyad as well as to other residues within the MPro active site with much greater affinity than penciclovir. The findings of the study suggest that these compounds could be explored as potential SARS-CoV-2 inhibitors, and could further be combined with the experimental investigations to develop effective therapeutics to deal with the present pandemic.
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Antivirales/farmacología , Productos Biológicos/farmacología , Proteasas 3C de Coronavirus/metabolismo , Fitoquímicos/farmacología , Inhibidores de Proteasas/farmacología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Antivirales/farmacocinética , Bacterias/metabolismo , Productos Biológicos/farmacocinética , Barrera Hematoencefálica/metabolismo , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Ciclopentanos/farmacocinética , Ciclopentanos/farmacología , Hongos/metabolismo , Humanos , Absorción Intestinal , Lactonas/farmacocinética , Lactonas/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oxilipinas/farmacocinética , Oxilipinas/farmacología , Fitoquímicos/farmacocinética , Plantas/metabolismo , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Dominios Proteicos , SARS-CoV-2RESUMEN
SRS27, an andrographolide analogue, had been proven to have therapeutic properties at a dose of 3 mg/kg in both in vitro and in vivo asthma models of our previous study. The present study focuses on the pharmacokinetic and toxicity profile of this compound to provide further evidence for the development of this compound as an anti-asthma agent. A simple pharmacokinetic study was performed in female BALB/c mice to measure blood plasma concentration of the compound at therapeutic dose. At a single dose of 3 mg/kg, SRS27 had a relatively short half-life but was able to achieve a concentration range of 13-19 µM that is related to its in vitro bioactivities. With regard to toxicity profile, SRS27 appears to be safe, as no histopathological changes were observed in the liver, kidneys and ovaries of SRS27-treated female BALB/c mice. In addition, there was no significant change in the mean body weight and organ weight of the animals in the SRS27-treated groups compared with the vehicle-treated control group at the end of the treatment. This fully supports the absence of any significant changes in peripheral blood leukocyte counts of SRS27-treated mice. Rewardingly, this acute toxicity study also revealed that SRS27 has a wide therapeutic window as no toxicity symptoms were detected with a dose up to 60 mg/kg daily when tested for 14 days. These results provide strong justification for further investigation of SRS27 as a potential new anti-asthma agent.
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Antiasmáticos/farmacocinética , Antiasmáticos/toxicidad , Diterpenos/farmacocinética , Diterpenos/toxicidad , Lactonas/farmacocinética , Lactonas/toxicidad , Animales , Antiasmáticos/sangre , Disponibilidad Biológica , Diterpenos/sangre , Femenino , Riñón/anatomía & histología , Riñón/efectos de los fármacos , Lactonas/sangre , Hígado/anatomía & histología , Hígado/efectos de los fármacos , Pulmón/anatomía & histología , Pulmón/efectos de los fármacos , Ratones Endogámicos BALB C , Ovario/anatomía & histología , Ovario/efectos de los fármacosRESUMEN
Free and glycosylated sesquiterpene lactones (SLs), which are abundant in leafy vegetables including Brussels/witloof chicory, possess health-promoting effects in vivo. However, the pharmacokinetics of dietary source of SLs remain largely unknown. In this open-label and single-dose trial, sixteen healthy volunteers consumed 150 g of Brussels/witloof chicory juice containing 48.77 µmol SLs in 5 min. Blood, urine, and fecal samples were collected before and after chicory consumption in 24 h. No SLs were detected in the serum, urine, and fecal samples before chicory consumption in all of the participants. Chicory consumption increased lactucin, 11ß,13-dihydrolactucin, and their glucuronide/sulfate conjugates, rather than lactucopicrin and 11ß,13-dihydrolactucopicrin, as well as glycosylated SLs in biological samples. The peak concentration of total SLs in serum reached 284.46 nmol/L at 1 h, while, in urine, this peak was 220.3 nmol between 2 and 6 h. The recovery of total SLs in blood, urine, and feces was 7.03%, 1.13%, and 43.76% of the ingested dose, respectively. Human fecal suspensions with intestinal microbiota degraded glycosylated SLs in chicory, and converted lactucopicrin and 11ß,13-dihydrolactucopicrin to lactucin and 11ß,13-dihydrolactucin, respectively. Collectively, Brussels/witloof chicory SLs are poorly bioavailable and they undergo partial gut microbial and phase II metabolism in humans.
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Brassica/química , Cichorium intybus/química , Jugos de Frutas y Vegetales/análisis , Microbioma Gastrointestinal , Lactonas/farmacocinética , Sesquiterpenos/farmacocinética , Administración Oral , Disponibilidad Biológica , Heces/microbiología , Humanos , Lactonas/química , Sesquiterpenos/químicaRESUMEN
PURPOSE: Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that is believed to function in a neuroprotective manner ideal for treating Parkinson's disease (PD). Despite its promising therapeutic properties, GB has poor bioavailability following oral administration and cannot readily achieve sufficient exposure in treated patients, limiting its clinical application for the treatment of PD. In an effort to improve its efficacy, we utilized poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) nanoparticles as a means of encapsulating GB (GB-NPs). These NPs facilitated the sustained release of GB into the blood, thereby improving its ability to accumulate in the brain and to treat PD. METHODS AND RESULTS: Using Madin-Darby canine kidney (MDCK) cells, we were able to confirm that these NPs could be taken into cells via multiple nonspecific mechanisms including micropinocytosis, clathrin-dependent endocytosis, and lipid raft/caveolae-mediated endocytosis. Once internalized, these NPs tended to accumulate in the endoplasmic reticulum and lysosomes. In zebrafish, we determined that these NPs were readily able to undergo transport across the chorion, gastrointestinal, blood-brain, and blood-retinal barriers. In a 1-methyl-4-phenylpyridinium ion (MPP+)-induced neuronal damage model system, we confirmed the neuroprotective potential of these NPs. Following oral administration to rats, GB-NPs exhibited more desirable pharmacokinetics than did free GB, achieving higher GB concentrations in both the brain and the blood. Using a murine PD model, we demonstrated that these GB-NPs achieved superior therapeutic efficacy and reduced toxicity relative to free GB. CONCLUSION: In conclusion, these results indicate that NPs encapsulation of GB can significantly improve its oral bioavailability, cerebral accumulation, and bioactivity via mediating its sustained release in vivo.
Asunto(s)
Ginkgólidos/administración & dosificación , Ginkgólidos/farmacología , Lactonas/administración & dosificación , Lactonas/farmacología , Nanopartículas/administración & dosificación , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Administración Oral , Animales , Disponibilidad Biológica , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Perros , Embrión no Mamífero/efectos de los fármacos , Glicoles de Etileno/química , Femenino , Ginkgólidos/farmacocinética , Humanos , Lactonas/farmacocinética , Células de Riñón Canino Madin Darby , Masculino , Ratones Endogámicos C57BL , Nanopartículas/química , Fármacos Neuroprotectores/administración & dosificación , Poliésteres/química , Ratas Sprague-Dawley , Pez Cebra/embriologíaRESUMEN
Atractylodis rhizoma is a frequently-used traditional Chinese medicine in clinical practice, which have the effect of eliminating dampness and tonifying spleen. And after being processed with wheat bran, the dryness of A. rhizoma is reduced, and the function of tonifying spleen is enhanced. Atractylenolides are the major bioactive components of A. rhizoma, including atractylenolide I (AI), atractylenolide â ¡ (Aâ ¡) and atractylenolide â ¢ (Aâ ¢). The present study aimed to develope a new UPLC-MS/MS method for simultaneous quantification of three atractylenolides in rat urine, and applied to the excretory kinetics in Sprague-Dawley rats after oral administration of crude and processed A. rhizoma extracts. Analytes and internal standard were detected without interference in the multiple reaction monitoring (MRM) mode with positive electrospray ionization. The excretory kinetics parameters were calculated by a urine drug analysis model of drug and statistics (DAS) 3.2.8 software. The t1/2 and Ke of three atractylenolides had no significant difference between crude and processed A. rhizoma, but the recovery accumulative excretion of them in processed A. rhizoma were apparently higher than the crude ones (p<0.05, p<0.01). The results showed that only a small amount of atractylenolides excreted in urine and processing A. rhizoma with wheat bran by stir frying could promote the urinary excretion of them.
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Atractylodes , Cromatografía Liquida , Lactonas/orina , Extractos Vegetales/orina , Eliminación Renal , Sesquiterpenos/orina , Espectrometría de Masas en Tándem , Administración Oral , Animales , Atractylodes/química , Lactonas/administración & dosificación , Lactonas/aislamiento & purificación , Lactonas/farmacocinética , Masculino , Modelos Biológicos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacocinética , Ratas Sprague-Dawley , Rizoma , Sesquiterpenos/administración & dosificación , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacocinéticaRESUMEN
Lekethromycin, a new macrolide lactone, exhibits significant antibacterial activity. In this study, a reliable analytical ultrahigh-performance liquid chromatography electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UPLC-ESI-Orbitrap-MS) method was established and validated for the detection of lekethromycin in rat plasma. After a simple acetonitrile (ACN)-mediated plasma protein precipitation, chromatographic separation was performed on a Phenomenex Luna Omega PS C18 column (30 × 2.1 mm i.d. particle size = 3 µm) conducted in a gradient elution procedure using 0.5% formic acid (FA) in ACN and 0.5% FA in water as the mobile phase pumped at a flow rate of 0.3 mL/min. Detection was carried out under positive electrospray ionization (ESI+) conditions in parallel reaction monitoring (PRM) mode with observation of m/z 804.5580 > 577.4056 for lekethromycin and 777.5471 > 619.4522 for gamithromycin (internal standard, IS). The linear range was 5-1000 ng/mL (r2 > 0.99), and the lower limit of quantification (LLOQ) was 5 ng/mL. The intra- and inter-day precision (expressed as relative standard deviation, RSD) values were ≤7.3% and ≤6.3%, respectively, and the accuracy was ≥90% ± 5.3%. The mean extraction recovery RSD valWeue was <5.1%. Matrix effects and dilution integrity RSD values were <5.6% and <3.2%, respectively. Lekethromycin was deemed stable under certain storage conditions. This fully validated method was effectively applied to study the pharmacokinetics of lekethromycin after a single intravenous administration of 5 mg/kg in rats. The main pharmacokinetic parameters were T1/2λz, CL_obs and VZ_obs were 32.33 ± 14.63 h, 0.58 ± 0.17 L/h/kg and 25.56 ± 7.93 L/kg, respectively.
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Cromatografía Líquida de Alta Presión/métodos , Macrólidos/sangre , Macrólidos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Intravenosa , Animales , Antibacterianos/sangre , Antibacterianos/farmacocinética , Calibración , Estabilidad de Medicamentos , Lactonas/sangre , Lactonas/farmacocinética , Masculino , Ratas Sprague-Dawley , Reproducibilidad de los ResultadosRESUMEN
SCOPE: Gut microbiota converts dietary phytochemicals into metabolites and modulates their health effects. The microbial metabolism of dietary terpenoids, as the sesquiterpene lactones of leafy vegetables, is unknown. METHODS AND RESULTS: In vitro fermentation of lactucopicrin, lactucin, and romaine lettuce with gut microbiota from independent donors, show their extensive metabolism through untargeted metabolomics of the fecal incubations. Dehydroxylations and double bond hydrogenations are the main catabolic reactions. Isomers of dihydrolactucopicrin, tetrahydrolactucopicrin, and deoxylactucin, are observed after lactucopicrin metabolism. Tetrahydrolactucin and hexahydrolactucin are also found after lactucin metabolism. Lettuce fermentation shows similar metabolic conversions. Phase II conjugates of most of these metabolites are detected in the urine of healthy volunteers after escarole salad intake. Glucuronides, and sulfates, of dihydrolactucopicrin, tetrahydrolactucopicrin, dihydrolactucin, and deoxylactucin, are detected in the urine although with large inter-subject variability. CONCLUSION: This is the first report on the gut microbiota metabolism of sesquiterpene lactones in humans, and one of the first reports to describe that dietary terpenoids of widely consumed leafy vegetables are extensively catabolized by human gut microbiota. A large inter-subject variation in the metabolism of sesquiterpene lactones also reflects differences in gut microbiota composition. It suggests that inter-individual differences in their health effects should be expected.
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Microbioma Gastrointestinal/fisiología , Lactonas/farmacocinética , Forboles/farmacocinética , Sesquiterpenos/farmacocinética , Adulto , Asteraceae/química , Heces/microbiología , Femenino , Fermentación , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Lactonas/metabolismo , Lactonas/orina , Lactuca/química , Masculino , Metabolómica/métodos , Forboles/metabolismo , Forboles/orina , Sesquiterpenos/metabolismo , Sesquiterpenos/orina , Verduras/químicaRESUMEN
Afidopyropen is an insecticide that acts as a TRPV channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including developmental toxicity in rats and rabbits. The GLP developmental toxicity study in rabbits did not produce evidence of maternal or fetal toxicity at the highest dose tested (32 mg/kg/day) but pharmacokinetics (PK) in pregnant rabbits in this study exhibited onset of PK nonlinearity from 5 mg/kg/day on, as measured by plasma Cmax and AUC. The NOAEL (32 mg/kg/day) is 9000X higher than maximum expected human dietary exposures to afidopyropen; the dose range where nonlinear PK were observed (5-15 mg/kg/day) is 1400-4200X higher. As nonlinearity occurred between 5 and 15 mg/kg/day, 32 mg/kg/day is concluded to be a sufficiently high dose (kinetically derived maximum dose) for a prenatal developmental toxicity study. As recognized by regulatory dose-selection guidance, onset of saturated PK is evidence of excessive biological stress to test animals rendering any effects at such doses of questionable relevance for human risk assessment. These data demonstrate that consideration of PK is critical for improving the dose-selection in developmental toxicity studies to enhance human relevance of animal toxicity studies.
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Compuestos Heterocíclicos de 4 o más Anillos/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Lactonas/metabolismo , Lactonas/farmacocinética , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Lactonas/administración & dosificación , Conformación Molecular , Embarazo , Conejos , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
As a major cause of neurodegeneration in the elderly, Parkinson's disease (PD) has attracted intense research attention. PD results from a decline in the numbers of dopaminergic neurons. Due to low levels of plasma exposure and the drug efflux properties of neuronal cells, orally delivering anti-PD drugs is challenging. Nanocrystals (NCs) can increase dissolution velocities and saturation solubility, improving oral bioavailability and brain uptake. In this study, Ginkgolide B (GB), a potent anti-Parkinsonism compound, was selected to verify the utility of NCs to effectively accumulate GB in both the blood and brain. Highly stabilized GB-NCs had small sizes, high rates of dissolution, enhanced cellular uptake and permeability. The GB-NCs could protect neurons against cytotoxicity induced by MPP+, and showed no toxicity in zebrafish. Fluorescent imaging in zebrafish indicated high levels of the NCs in both the gut and brain. When orally administrated to rats, the GB-NCs showed higher drug plasma levels and neuronal drug distributions when compared to control groups. Importantly, in MPTP-induced PD model, GB-NCs treatment resulted in improved behavior, reduced dopamine deficiency, and elevated dopamine metabolite levels. In summary, these highlight the fabrication of GB-NCs as effective drug carriers for the neuronal delivery of anti-PD therapies.