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1.
J Agric Food Chem ; 68(6): 1563-1570, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927998

RESUMO

Ethanamizuril(N-{4-[4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenoxy]-phenyl}-acetamide, EZL) is a new anticoccidiosis compound and belongs to the class of triazines. In this study, the metabolism, distribution, and excretion of EZL were evaluated in chickens after administration of EZL at a single dosage. According to the relevant drug biotransformation rules, the exact molecular mass detection, the fragmentation characteristics, and the retention times, a total of five metabolites were identified in vivo in chickens, including two phase I metabolites and three phase II conjugated metabolites. The major metabolic pathways of EZL in chickens were deacetylation, hydroxylation, and glucuronidation. Regarding 14C-tissue residues after administration, kidney was considered to be the target tissue, as 14C-tissue residues could be detected at 240 h postdose. DeacetylEZL (M3) was the main metabolite, accounting for 68.65% and 25.62% of 14C in kidney at 6 and 24 h, respectively. In heart, muscle, skin+fat, and lung tissues, EZL was the main radioactive substance accounting for 94.88%, 97.32%, 96.23%, and 91.3% of 14C, respectively. In the liver, EZL and M3 were 20.76% and 54.65% of 14C, respectively. In chicken tissues the ratio of M5 was too low to be quantitated and it was mainly detected in chicken fecal and bile samples. In chicken excreta, EZL, M3, and glucuronidation of EZL (M5) accounted for 7.02%, 12.33%, and 10.32% of the dose, respectively and were eliminated primarily. This study presents the first detection of EZL metabolites, which is helpful for further understanding of the metabolic mechanism and in vivo intermediate processes of EZL. The results of this study will be good bases for better understanding EZL's anticoccidiosis mechanism and will serve as a helpful reference for assessing the risks to animals and humans.


Assuntos
Coccidiostáticos/farmacocinética , Triazinas/farmacocinética , Animais , Biotransformação , Galinhas , Coccidiostáticos/administração & dosagem , Coccidiostáticos/metabolismo , Hidroxilação , Rim/química , Rim/metabolismo , Fígado/química , Fígado/metabolismo , Pulmão/química , Pulmão/metabolismo , Músculos/química , Músculos/metabolismo , Triazinas/administração & dosagem , Triazinas/metabolismo
2.
Cancer Sci ; 111(2): 536-547, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778267

RESUMO

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).


Assuntos
Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Triazinas/administração & dosagem , Idoso , Cápsulas , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Comprimidos , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
3.
Toxicol Lett ; 318: 50-56, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31622650

RESUMO

The development of three generic multi-compartment physiologically based kinetic (PBK) models is described for farm animal species, i.e. cattle, sheep, and swine. The PBK models allow one to quantitatively link external dose and internal dose for risk assessment of chemicals relevant to food and feed safety. Model performance is illustrated by predicting tissue concentrations of melamine and oxytetracycline and validated through comparison with measured data. Overall, model predictions were reliable with 71% of predictions within a 3-fold of the measured data for all three species and only 6% of predictions were outside a 10-fold of the measured data. Predictions within a 3-fold change were best for cattle, followed by sheep, and swine (82%, 76%, and 63%). Global sensitivity analysis was performed to identify the most sensitive parameters in the PBK model. The sensitivity analysis showed that body weight and cardiac output were the most sensitive parameters. Since interspecies differences in metabolism impact on the fate of a wide range of chemicals, a key step forward is the introduction of species-specific information on transporters and metabolism including expression and activities.


Assuntos
Ração Animal , Gado/metabolismo , Modelos Biológicos , Oxitetraciclina/farmacocinética , Triazinas/farmacocinética , Ração Animal/toxicidade , Animais , Bovinos , Oxitetraciclina/administração & dosagem , Oxitetraciclina/efeitos adversos , Reprodutibilidade dos Testes , Carneiro Doméstico , Especificidade da Espécie , Sus scrofa , Distribuição Tecidual , Triazinas/administração & dosagem , Triazinas/toxicidade
4.
Expert Opin Pharmacother ; 20(16): 1935-1942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454277

RESUMO

Introduction: Despite recent progress, the prognosis of acute myeloid leukemia remains poor, mainly in older and in relapsed/refractory patients. Recently, a large number of novel agents have been developed thanks to a better understanding of its pathogenesis. Among these, the potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib (formerly AG-221), has demonstrated promising antileukemic activity by targeting IDH2 mutations. Area covered: This review describes the mechanisms of action, the pharmacodynamic and pharmacokinetic properties, the safety, and efficacy of enasidenib. Phase I/II/III clinical trials are also reported and discussed. Expert opinion: Enasidenib is a novel agent able to differentiate leukemic blasts in functional, maturating cells. This drug is characterized by oral bioavailability and good tolerability. As a monotherapy, it demonstrates clinical and laboratorial improvement, in 19.6% and 38.8% of cases respectively. Differentiation syndrome is the most relevant, potentially life-threatening side effect, which physicians must be aware of. The authors believe that the way forwards now is to explore the role of enasidenib as a chemoresistance revertant when associated with chemotherapy, as a 'bridge to transplant' or when associated other novel agents if we wish to maximize its use.


Assuntos
Aminopiridinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/uso terapêutico , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Ensaios Clínicos como Assunto , Aprovação de Drogas , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Prognóstico , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
5.
Biomed Chromatogr ; 33(11): e4658, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325170

RESUMO

Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2  = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Piridinas/sangue , Triazinas/sangue , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Estabilidade de Medicamentos , Glicina/sangue , Glicina/química , Glicina/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Piridinas/química , Piridinas/farmacocinética , Reprodutibilidade dos Testes , Triazinas/química , Triazinas/farmacocinética
6.
Biomed Chromatogr ; 33(11): e4652, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322281

RESUMO

Ethanamizuril is a new triazine compound that has the potential to be a novel anticoccidial drug. Toxicological studies in experimental rats were performed to understand the safety profile of ethanamizuril for drug product development. In this study, a novel, selective and accurate ultra-performance liquid chromatography tandem mass spectrometry method has been developed for the determination of ethanamizuril concentrations in rat plasma. With 4-nitro-o-cresol as an internal standard, sample pretreatment involved a one-step extraction with acetonitrile of 100 µL plasma. The detection was carried out by electrospray ionization mass spectrometry in negative ion mode with selected ion recording. The standard curves were linear (r2 ≥ 0.999) over the concentration range of 0.1-100 µg/mL. The relative standard deviations of intra- and inter-day precisions were less than 8.4 and 8.87%, respectively. The mean extraction recovery of ethanamizuril from rat plasma was 97.68-102.57%. The method was fully validated and successfully applied to monitor plasma concentrations of ethanamizuril in a short-term toxicity study and two-generation reproduction toxicity study. The result of the study confirmed that the elimination of ethanamizuril in rats is slow.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Coccidiostáticos/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Animais , Coccidiostáticos/química , Coccidiostáticos/farmacocinética , Feminino , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Triazinas/química , Triazinas/farmacocinética
7.
Eur J Pharm Sci ; 136: 104938, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132401

RESUMO

Savolitinib is a novel small-molecule selective cMet inhibitor. This work characterized its pharmacokinetics in preclinical phase, established the preclinical relationships between PK, cMet modulation and anti-tumor efficacy. In vitro and in vivo animal studies were performed for PK characterization. Savolitinib showed good absorption, moderate tissue distribution, low to intermediate clearance, and low accumulation. Hepatic oxidative metabolism followed by urinary and biliary excretions was the major elimination pathway. Based on preclinical PK data, human PK profiles were predicted using empirical methods. Pharmacodynamic studies for evaluating cMet inhibition and anti-tumor efficacy were conducted in nude mice bearing Hs746t xenograft. PK/PD models were built to link the PD measurements to nude mouse PK. The established integrated preclinical PK/PD model contained a two-compartment non-linear PK model, a biomarker link model and a tumor growth transit model. The IC50 of cMet inhibition and the concentration achieving half of the maximal Hs746t tumor reduction by savolitinib were equal to 12.5 and 3.7 nM (free drug), respectively. Based on the predicted human PK data, as well as the established PK/PD model in nude mouse, the human PD (cMet inhibition) profiles were also simulated. This research supported clinical development of savolitinib. Understanding the preclinical PK/PD relationship of savolitinib provides translational insights into the cMet-targeted drug development.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/farmacologia , Pirazinas/farmacocinética , Triazinas/farmacologia , Triazinas/farmacocinética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Modelos Biológicos , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1118-1119: 203-209, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31059927

RESUMO

A convenient, simple, selective and reliable method was established for separating diclazuril enantiomers and detecting their residues in chicken edible tissues by using high-performance liquid chromatography. The potential effects of chiral column, mobile phase and column temperature on chiral separation of racemic diclazuril were evaluated. Average recovery rates of R-diclazuril and S-diclazuril in three spiking levels ranged from 84.3% to 109.5%, and the relative standard deviations were <15.8%. The limits of quantification of two enantiomers were all 25 ng g-1 in all chicken tissues. The method proposed was successfully applied to monitor distributions and residue elimination of diclazuril enantiomers in chicken muscle, liver, kidney and fat following oral administration. There are no obvious differences (p > 0.05) between R-diclazuril and S-diclazuril in the same tissue for each sampling time. The elimination rates in liver were the fastest and the residual time in kidney was the longest. These results can help further evaluate pharmokinetics, pharmodynamics and toxicity of each enantiomer of diclazuril in food-producing animals.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Resíduos de Drogas/análise , Carne/análise , Nitrilos/análise , Triazinas/análise , Animais , Galinhas , Resíduos de Drogas/química , Resíduos de Drogas/farmacocinética , Limite de Detecção , Modelos Lineares , Nitrilos/química , Nitrilos/farmacocinética , Reprodutibilidade dos Testes , Estereoisomerismo , Distribuição Tecidual , Triazinas/química , Triazinas/farmacocinética
9.
Environ Sci Pollut Res Int ; 26(16): 15838-15846, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953324

RESUMO

1,3,5-Tris-(2,3-dibromopropyl)-1,3,5-triazine-2,4,6-trione (TDBP-TAZTO) is an emerging brominated flame retardant which is widely used in several plastic materials (electric and electronic equipment, musical instruments, automotive components). However, until today, no photochemical studies as well as the identification of possible phototransformation products (PTPs) were described in literature. Therefore, in this study, UV-(C) and simulated sunlight irradiation experiments were performed to investigate the photolytic degradation of TDBP-TAZTO and to identify relevant PTPs for the first time. The UV-(C) irradiation experiments show that the photolysis reaction follows a first-order kinetic model. Based on this, the photolysis rate constant k as well as the half-life time t1/2 were calculated to be k = (41 ± 5 × 10-3) min-1 and t1/2 = (17 ± 2) min. In comparison, a minor degradation of TDBP-TAZTO and no formed phototransformation products were obtained under simulated sunlight. In order to clarify the photochemical behavior, different chemicals were added to investigate the influence on indirect photolysis: (i) H2O2 for generation of hydroxyl radicals and (ii) two quenchers (2-propanol, sodium azide) for scavenging oxygen species which were formed during the irradiation experiments. Herein, nine previously unknown PTPs of TDBP-TAZTO were detected under UV-(C) irradiation and identified by HPLC-(HR)MS. As a result, debromination, hydroxylation, and dehydrobromination reactions could be presumed as the main degradation pathways by high-resolution mass spectrometry. The direct as well as the OH radical-induced indirect photolysis were observed. Graphical abstract .


Assuntos
Retardadores de Chama/farmacocinética , Peróxido de Hidrogênio/química , Triazinas/farmacocinética , Halogenação , Cinética , Espectrometria de Massas , Fotólise , Luz Solar , Triazinas/análise , Triazinas/química
11.
Nanoscale ; 11(7): 3326-3335, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30724283

RESUMO

The endoplasmic reticulum (ER) is one of the most important organelles controlling myriads of cellular functions including protein folding/misfolding/unfolding, calcium ion homeostasis and lipid biosynthesis. Subsequently, due to its functional dysregulation in cancer cells, it has emerged as an interesting target for anti-cancer therapy. However, specific targeting of the ER in cancer cells remains a major challenge due to the lack of ER-selective chemical tools. Furthermore, for performing multiple cellular functions the ER is dependent on the nucleus through complicated cross-talk. Herein, we have engineered a supramolecular self-assembled hexameric rosette structure from two small molecules: tri-substituted triazine and 5-fluorouracil (5-FU). This rosette structure consists of an ER-targeting moiety with a fluorescence tag, an ER-stress inducer and a nuclear DNA damaging drug simultaneously, which further self-assembled into an ER-targeting spherical nano-scale particle (ER-NP). These ER-NPs internalized into HeLa cervical cancer cells by macropinocytosis and specifically localized into the ER to induce ER stress and DNA damage leading to cell death through apoptosis. Interestingly, ER-NPs initiated autophagy, inhibited by a combination of ER-NPs and chloroquine (CQ) to augment cancer cell death. This work has the potential to exploit the concept of supramolecular self-assembly into developing novel nano-scale materials for specific sub-cellular targeting of multiple organelles for future anti-cancer therapy.


Assuntos
Cloroquina , Sistemas de Liberação de Medicamentos/métodos , Retículo Endoplasmático/metabolismo , Fluoruracila , Neoplasias , Triazinas , Cloroquina/farmacocinética , Cloroquina/farmacologia , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Células HeLa , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Triazinas/farmacocinética , Triazinas/farmacologia
12.
Cancer Sci ; 110(4): 1340-1351, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30724423

RESUMO

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug-related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.


Assuntos
Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Triazinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/mortalidade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Análise de Sobrevida , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
13.
Int J Toxicol ; 38(2): 110-120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30760067

RESUMO

Pexacerfont is a corticotropin-releasing factor subtype 1 receptor antagonist that was developed for the treatment of anxiety- and stress-related disorders. This report describes the results of repeat-dose oral toxicity studies in rats (3 and 6 months) and dogs (3 months and 1 year). Pexacerfont was well tolerated in all of these studies at exposures equal to or greater than areas under the curve in humans (clinical dose of 100 mg). Microscopic changes in the liver (hepatocellular hypertrophy), thyroid glands (hypertrophy/hyperplasia and adenomas of follicular cells), and pituitary (hypertrophy/hyperplasia and vacuolation of thyrotrophs) were only observed in rats and were considered adaptive changes in response to hepatic enzyme induction and subsequent alterations in serum thyroid hormone levels. Evidence for hepatic enzyme induction in dogs was limited to increased liver weights and reduced thyroxine (T4) levels. Mammary gland hyperplasia and altered female estrous cycling were only observed in rats, whereas adverse testicular effects (consistent with minimal to moderate degeneration of the germinal epithelium) were only noted following chronic dosing in dogs. The testicular effects were reversible changes with exposure margins of 8× at the no observed adverse effect level. It is not clear whether the changes in mammary gland, estrous cycling, and testes represent secondary hormonal changes due to perturbation of the hypothalamic-pituitary-adrenal axis or are off-target effects. In conclusion, the results of chronic toxicity studies in rats and dogs show that pexacerfont has an acceptable safety profile to support further clinical testing.


Assuntos
Pirazóis/toxicidade , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/toxicidade , Administração Oral , Animais , Cães , Feminino , Masculino , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Pirazóis/farmacocinética , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/patologia , Testes de Toxicidade Crônica , Testes de Toxicidade Subcrônica , Triazinas/farmacocinética
14.
Phytomedicine ; 53: 243-251, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30668404

RESUMO

BACKGROUND: Astragalosidic acid (LS-102) is a new water-soluble derivative of astragaloside IV - a major effective component isolated from the Chinese herb Astragali Radix. Our previous study showed that LS-102 exhibited potent cardiovascular activity. PURPOSE: The objective of this study was to investigate the pharmacokinetic properties of LS-102 after single-dose, oral administration in beagle dogs by developing and validating an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. METHOD AND RESULT: The chromatographic separation was performed on a Acquity HSS C18 column (100 mm × 2.1 mm, 1.8 µm) by a gradient elution using a mobile phase consisting of water and acetonitrile at a flow rate of 0.35 ml/min. The analytes were detected with a triple quadrupole tandem mass spectrometry in multiple reaction monitoring mode. Method validation revealed a wide linearity over the range of 2.0-10,000 ng/ml together with satisfactory intra- and inter-day precision, accuracy, and recovery. Stability testing showed that LS-102 spiked into dog plasma was stable for 4 h at room temperature, for up to 2 weeks at -80 °C, and during three freeze-thaw cycles. The method was effectively and successfully applied to the pharmacokinetics of LS-102 after oral administration (5, 10 and 20 mg/kg) to beagle dogs. Peak plasma concentrations are attained within approximately 2 h after oral administration with a half-life ranging from 1.55 h to 4.49 h. The plasma concentration-time curve of LS-102 after oral administration presents the phenomenon of a double-peak absorption phase. The peak concentration and area under the concentration-time curve of LS-102 seemed to increase with the increasing doses proportionally, that suggesting linear pharmacokinetics in dogs. Meanwhile, the doxorubicin (Dox)-injured H9c2 cell model was prepared by incubating the cells in 1 µM Dox for 24 h. MTT assay and LDH release measurement showed that LS-102 protected against Dox-induced cardiomyocyte death. CONCLUSION: The obtained results may help to guide the further pre-clinical research of LS-102 as a potentially novel cardioprotective agent.


Assuntos
Benzoxazóis/sangue , Benzoxazóis/farmacocinética , Cromatografia Líquida/métodos , Saponinas/química , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Triazinas/farmacocinética , Triterpenos/química , Administração Oral , Animais , Benzoxazóis/administração & dosagem , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Cães , Doxorrubicina/efeitos adversos , Estabilidade de Medicamentos , Medicamentos de Ervas Chinesas/química , Feminino , Meia-Vida , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Reprodutibilidade dos Testes , Triazinas/administração & dosagem
15.
Biomed Chromatogr ; 33(6): e4491, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30663096

RESUMO

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guidelines for the estimation of enasidenib on mouse dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The method employs liquid extraction of enasidenib from DBS disks of mouse whole blood followed by chromatographic separation using 0.2% formic acid-acetonitrile (25:75, v/v) at a flow rate of 1.0 mL/min on an Atlantis dC18 column with a total run time of 2.0 min. The MS/MS ion transitions monitored were m/z 474.0 → 267.1 for enasidenib and m/z 309.2 → 251.3 for the internal standard (warfarin). The assay was linear in the range of 1.01-3044 ng/mL. The within-run and between-run precisions were in the range of 3.18-9.06 and 4.66-8.69%, respectively. Stability studies showed that enasidenib was stable on DBS cards for 1 month. This novel method has been applied to analyze the DBS samples of enasidenib obtained from a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Triazinas/farmacocinética , Aminopiridinas/química , Animais , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Reprodutibilidade dos Testes , Triazinas/química
16.
Clin Pharmacol Ther ; 105(1): 190-200, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29882324

RESUMO

Cycloguanil, the active metabolite of proguanil, acts on malaria schizonts in erythrocytes and hepatocytes. We analyzed the impact of the organic cation transporter OCT1 on hepatocellular uptake and pharmacokinetics of proguanil and cycloguanil. OCT1 transported both proguanil and cycloguanil. Common variants OCT1*3 and OCT1*4 caused a substantial decrease and OCT1*5 and OCT1*6 complete abolishment of proguanil uptake. In 39 healthy subjects, low-activity variants OCT1*3 and OCT1*4 had only minor effects on proguanil pharmacokinetics. However, both, cycloguanil area under the time-concentration curve and the cycloguanil-to-proguanil ratio were significantly dependent on number of these low-functional alleles (P = 0.02 for both). Together, CYP2C19, CYP3A5, OCT1 polymorphisms, and sex accounted for 61% of the variation in the cycloguanil-to-proguanil ratio. Most importantly, in vitro OCT1 inhibition caused a fivefold decrease of intracellular cycloguanil concentrations in primary human hepatocytes. In conclusion, OCT1-mediated uptake is a limiting step in bioactivation of proguanil, and OCT1 polymorphisms may affect proguanil efficacy against hepatic malaria schizonts.


Assuntos
Antimaláricos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fator 1 de Transcrição de Octâmero/deficiência , Proguanil/metabolismo , Triazinas/metabolismo , Adolescente , Adulto , Antimaláricos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Proguanil/farmacocinética , Triazinas/farmacocinética , Adulto Jovem
17.
Xenobiotica ; 49(2): 200-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29320949

RESUMO

1. The absorption, distribution, metabolism and excretion of enasidenib were studied following a single oral dose of [14C]enasidenib to rats (10 mg/kg; 100 µCi/kg) and healthy volunteers (100 mg; 318 nCi). 2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95-99% of the dose from rats in 168 h post-dose and 82.4% from human volunteers in 504 h post-dose. In rat bile, approximately 35-42% of the administered dose was recovered, with less than 5% of the dose excreted as the parent drug. Renal elimination was a minor pathway, with <12% of the dose excreted in rat urine and <10% of the dose excreted in human urine. 3. Enasidenib was the prominent radioactive component in rat and human systemic circulation. Enasidenib was extensively metabolized in rats and human volunteers through N-dealkylation, oxidation, direct glucuronidation and combinations of these pathways. Glucuronidation was the major metabolic pathway in rats while N-dealkylation was the prominent metabolic pathway in human volunteers. All human metabolites were detected in rats.


Assuntos
Aminopiridinas/farmacocinética , Antineoplásicos/farmacocinética , Triazinas/farmacocinética , Aminopiridinas/sangue , Aminopiridinas/urina , Animais , Antineoplásicos/sangue , Antineoplásicos/urina , Bile/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Rim/metabolismo , Fígado/metabolismo , Redes e Vias Metabólicas , Ratos , Espectrometria de Massas em Tandem , Triazinas/sangue , Triazinas/urina
18.
Eur J Drug Metab Pharmacokinet ; 44(2): 251-259, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30315409

RESUMO

BACKGROUND AND OBJECTIVES: Astragaloside IV (AGS IV) is the most important bioactive constituent of Radix Astragali. However, its disappointing clinical application is mainly caused by its very low solubility in biologic fluids, resulting in poor bioavailability after oral administration. We recently obtained a novel water-soluble derivative of AGS IV (astragalosidic acid, LS-102) that displayed significant cardioprotective potential against hypoxia-induced injury. The objective of this study was to investigate the intestinal absorption, main pharmacokinetic parameters and acute toxicity of LS-102 in rodents compared with AGS IV. METHODS: An oral dose of LS-102 and AGS IV (20 mg/kg) was administered to Sprague-Dawley (SD) rats, and blood samples were collected at predetermined time points. The plasma concentrations were detected by a validated UHPLC-MS/MS method, and pharmacokinetic parameters were calculated using a compartmental model. In the intestinal permeability study, the transport of LS-102 across Caco-2 cell monolayers was investigated at six concentrations from 6.25 to 250 µM. Moreover, the acute toxicity of LS-102 (40-5000 mg/kg) via a single oral administration was investigated in BALB/c mice. RESULTS: LS-102 was rapidly absorbed, attaining a maximum concentration of 248.7 ± 22.0 ng/ml at 1.0 ± 0.5 h after oral administration. The relative bioavailability of LS-102 was twice that of AGS IV. LS-102 had a Papp (mean) of 15.72-25.50 × 10-6 cm/s, which was almost 500-fold higher than that of AGS IV, showing that LS-102 had better transepithelial permeability and could be better absorbed in the intestinal tract. The acute toxicity study showed no abnormal changes or mortality in mice treated with LS-102 even at the single high dose of 5000 mg/kg body weight. CONCLUSIONS: Oral LS-102 produced a pharmacokinetic profile different from AGS IV with higher bioavailability, while the toxic tolerance was similar to previous estimates. Thus, we speculated that LS-102 might provide better clinical efficacy and be a potential candidate for the new drug development of Radix Astragali.


Assuntos
Benzoxazóis/farmacocinética , Benzoxazóis/toxicidade , Absorção Intestinal/efeitos dos fármacos , Triazinas/farmacocinética , Triazinas/toxicidade , Administração Oral , Animais , Benzoxazóis/análise , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Células CACO-2 , Feminino , Humanos , Absorção Intestinal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Saponinas/análise , Saponinas/farmacocinética , Saponinas/toxicidade , Solubilidade , Espectrometria de Massas em Tandem/métodos , Triazinas/análise , Triterpenos/análise , Triterpenos/farmacocinética , Triterpenos/toxicidade , Água/metabolismo
19.
Xenobiotica ; 49(10): 1229-1236, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30394160

RESUMO

1. The present study investigated inhibitory effects of enasidenib and its metabolite AGI-16903 on (a) recombinant human nucleoside transporters (hNTs) in hNT-producing Xenopus laevis oocytes, and (b) azacitidine uptake in a normal B-lymphoblast peripheral blood cell line (PBC) and acute myeloid leukemia (AML) cell lines. 2. Enasidenib inhibited hENT1, hENT2, hENT3, and hENT4 in oocytes with IC50 values of 7, 63, 27, and 76 µM, respectively, but exhibited little inhibition of hCNT1-3. AGI-16903 exhibited little inhibition of any hNT produced in oocytes. 3. Azacitidine uptake was more than 2-fold higher in AML cells than in PBC. Enasidenib inhibited azacitidine uptake into OCI-AML2, TF-1 and PBC cells in a concentration-dependent manner with IC50 values of 0.27, 1.7, and 1.0 µM in sodium-containing transport medium, respectively. 4. IC50 values shifted approximately 100-fold higher when human plasma was used as the incubation medium (27 µM in OCI-AML2, 162 µM in TF-1, and 129 µM in PBC), likely due to high human plasma protein binding of enasidenib (98.5% bound). 5. Although enasidenib inhibits hENTs and azacitidine uptake in vitro, plasma proteins attenuate this inhibitory effect, likely resulting in no meaningful in vivo effects in humans.


Assuntos
Aminopiridinas , Azacitidina , Isocitrato Desidrogenase/antagonistas & inibidores , Proteínas de Transporte de Nucleosídeos/metabolismo , Triazinas , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Azacitidina/farmacocinética , Azacitidina/farmacologia , Linhagem Celular , Humanos , Proteínas de Transporte de Nucleosídeos/genética , Triazinas/farmacocinética , Triazinas/farmacologia , Xenopus laevis
20.
Vet J ; 242: 74-76, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30503548

RESUMO

The purpose of this study was to determine if a low dose of diclazuril (0.5mg/kg of 1.56% diclazuril pellets) given to six healthy adult horses every 3-4 days for a total of five administrations would achieve steady-state plasma concentrations known to be inhibitory to Sarcocystis neurona and Neospora caninum. Blood was collected via venipuncture immediately before (trough concentrations) and 10h after (peak concentrations) each diclazuril administration and analysed by high-pressure liquid chromatography. The mean population-derived peak concentration was 0.284µg/mL and the mean terminal half-life was 1.6 days, but with a large variation. Thus, low dose diclazuril pellets produce steady-state plasma drug concentrations known to inhibit S. neurona (0.001µg/mL) and N. caninum (0.1µg/mL).


Assuntos
Coccidiostáticos/farmacocinética , Cavalos/metabolismo , Nitrilos/farmacocinética , Triazinas/farmacocinética , Administração Oral , Animais , Coccidiostáticos/administração & dosagem , Coccidiostáticos/sangue , Esquema de Medicação , Feminino , Cavalos/sangue , Masculino , Nitrilos/administração & dosagem , Nitrilos/sangue , Triazinas/administração & dosagem , Triazinas/sangue
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