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1.
Pharmacol Res Perspect ; 9(2): e00743, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33710753

RESUMO

Both antiviral treatment with remdesivir and hemoadsorption using a CytoSorb® adsorption device are applied in the treatment of severe COVID-19. The CytoSorb® adsorber consists of porous polymer beads that adsorb a broad range of molecules, including cytokines but also several therapeutic drugs. In this study, we evaluated whether remdesivir and its main active metabolite GS-441524 would be adsorbed by CytoSorb® . Serum containing remdesivir or GS-441524 was circulated in a custom-made system containing a CytoSorb® device. Concentrations of remdesivir and GS-441524 before and after the adsorber were analyzed by liquid chromatography-tandem mass spectrometry. Measurements of remdesivir in the outgoing tube after the adsorber indicated almost complete removal of remdesivir by the device. In the reservoir, concentration of remdesivir showed an exponential decay and was not longer detectable after 60 mins. GS-441524 showed a similar exponential decay but, unlike remdesivir, it reached an adsorption-desorption equilibrium at ~48 µg/L. Remdesivir and its main active metabolite GS-441524 are rapidly eliminated from the perfusate by the CytoSorb® adsorber device in vitro. This should be considered in patients for whom both therapies are indicated, and simultaneous application should be avoided. In general, plasma levels of therapeutic drugs should be closely monitored under concurrent CytoSorb® therapy.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Hemoperfusão/instrumentação , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Análise Química do Sangue , Cromatografia Líquida , Terapia Combinada , Furanos/sangue , Furanos/farmacocinética , Hemoperfusão/efeitos adversos , Humanos , Pirróis/sangue , Pirróis/farmacocinética , Espectrometria de Massas em Tandem , Triazinas/sangue , Triazinas/farmacocinética
2.
Eur J Drug Metab Pharmacokinet ; 45(6): 725-733, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32860624

RESUMO

BACKGROUND AND OBJECTIVE: Imeglimin is a novel oral antidiabetic drug to treat type 2 diabetes, targeting the mitochondrial bioenergetics. In vitro, imeglimin was shown to be a substrate of human multidrug and toxic extrusion transporters MATE1 and MATE2-K and organic cation transporters OCT1 and OCT2. The objective of the study was to assess the potential drug-drug interaction between imeglimin and cimetidine, a reference inhibitor of these transporters. METHODS: A phase 1 study was carried out in 16 subjects who received a single dose of 1500 mg imeglimin alone on day 1 followed by a 6-day treatment (day 5 to day 10) with cimetidine 400 mg twice daily. On day 8, a single dose of imeglimin was co-administered with cimetidine. Blood and urine samples were collected up to 72 h after each imeglimin administration. Pharmacokinetic parameters were determined using non-compartmental methods. RESULTS: Imeglimin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 1.3-fold [90% CI (1.12-1.62) and (1.10-1.46) for Cmax and AUC0-last, respectively] higher when imeglimin was co-administered with cimetidine but this increase was not considered clinically relevant. This increase could be mainly explained by a reduction in renal elimination, mediated through the cimetidine inhibition of renal MATE1 transporter. Imeglimin taken alone or with cimetidine was safe and well tolerated in all subjects. CONCLUSIONS: No clinically significant drug-drug interaction exists between imeglimin and cimetidine, a reference inhibitor of MATE1, MATE2-K, OCT1 and OCT2 transporters. CLINICAL TRIAL REGISTRATION: EudraCT 2018-001103-36.


Assuntos
Cimetidina/farmacologia , Antagonistas dos Receptores Histamínicos H2/farmacologia , Hipoglicemiantes/farmacocinética , Rim/metabolismo , Triazinas/farmacocinética , Adulto , Área Sob a Curva , Interações Medicamentosas , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fator 1 de Transcrição de Octâmero/antagonistas & inibidores , Fator 1 de Transcrição de Octâmero/metabolismo , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Transportador 2 de Cátion Orgânico/metabolismo , Adulto Jovem
3.
Clin Chem Lab Med ; 58(9): 1461-1468, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32573468

RESUMO

Objectives: A method based on liquid chromatography coupled to triple quadrupole mass spectrometry detection using 50 µL of plasma was developed and fully validated for quantification of remdesivir and its active metabolites GS-441524. Methods: A simple protein precipitation was carried out using 75 µL of methanol containing the internal standard (IS) remdesivir-13C6 and 5 µL ZnSO4 1 M. After separation on Kinetex® 2.6 µm Polar C18 100A LC column (100 × 2.1 mm i.d.), both compounds were detected by a mass spectrometer with electrospray ionization in positive mode. The ion transitions used were m/z 603.3 â†’ m/z 200.0 and m/z 229.0 for remdesivir, m/z 292.2 â†’ m/z 173.1 and m/z 147.1 for GS-441524 and m/z 609.3 â†’ m/z 206.0 for remdesivir-13C6. Results: Calibration curves were linear in the 1-5000 µg/L range for remdesivir and 5-2500 for GS-441524, with limit of detection set at 0.5 and 2 µg/L and limit of quantification at 1 and 5 µg/L, respectively. Precisions evaluated at 2.5, 400 and 4000 µg/L for remdesivir and 12.5, 125, 2000 µg/L for GS-441524 were lower than 14.7% and accuracy was in the [89.6-110.2%] range. A slight matrix effect was observed, compensated by IS. Higher stability of remdesivir and metabolite was observed on NaF-plasma. After 200 mg IV single administration, remdesivir concentration decrease rapidly with a half-life less than 1 h while GS-441524 appeared rapidly and decreased slowly until H24 with a half-life around 12 h. Conclusions: This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , Betacoronavirus , Cromatografia Líquida/métodos , Infecções por Coronavirus/sangue , Monitoramento de Medicamentos/métodos , Furanos/sangue , Pneumonia Viral/sangue , Pirróis/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Antivirais/farmacocinética , Estabilidade de Medicamentos , Feminino , Furanos/farmacocinética , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Pandemias , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Triazinas/farmacocinética
4.
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
5.
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
6.
Biomed Chromatogr ; 34(3): e4768, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31821576

RESUMO

A highly sensitive, specific and simple LC-MS/MS method for quantification of capmatinib (INC280) in rat plasma was presented. The LC-MS/MS method was validated in terms of specificity and selectivity, linearity, accuracy and precision, matrix effect, extraction recovery, dilution integrity, carryover and stability as per the US Food and Drug Administration's bioanalytical method validation guideline. The validated assay was applied for quantification of capmatinib from a pharmacokinetic study in rats following oral administration at the doses of 1.0, 3.0 and 9.0 mg/kg. The calibration curve ranges from 1 to 2000 ng/ml with desirable linearity and r2 > 0.99. The intra- and inter-batch accuracies were within 99.24-103.59 and 97.76-102.83% with coefficients of variation 5.08-7.36 and 3.18-4.99%, respectively. No significant interference was observed by endogenous peak at the retention time of capmatinib and IS. The assay was free from any matrix effect and showed precise recovery across the calibration curve range, and samples were stable under all experimental conditions. The validated assay was successfully applied to analyze plasma samples of pharmacokinetic study in rat to determine the concentration of capmatinib. In summary, a novel method for analyzing capmatinib in rat plasma has been successfully validated and is now being utilized for quantification of capmatinib from pre-clinical studies.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Imidazóis/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Administração Oral , Animais , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Triazinas/administração & dosagem , Triazinas/farmacocinética
7.
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
8.
Drug Res (Stuttg) ; 70(1): 41-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31652462

RESUMO

Enasidenib is a selective mutant isocitrate dehydrogenase 2 inhibitor approved for the treatment of relapsed and refractory acute myeloid leukemia patients. A sensitive and rapid method has been developed and validated as per regulatory guideline for the simultaneous quantitation of enasidenib and its active metabolite, AGI-16903 in mice plasma using an LC-MS/MS. Enasidenib and AGI-16903 along with internal standard were extracted from mice plasma using simple protein precipitation method. Chromatographic resolution of enasidenib, AGI-16903 and the internal standard (close analogue of AGI-16903) was achieved on a Chromolith RP-18e column using 0.2% formic acid:acetonitrile (15:85, v/v) as an eluent, which was delivered at a flow-rate of 1.2 mL/min. The MS/MS ion transitions monitored were m/z 474.1→267.2, 402.1→188.1 and 421.0→146.1 for enasidenib, AGI-16903 and the internal standard, respectively. The linearity range was 1.01-3023 ng/mL for both enasidenib and AGI-16903. The within-run and between-run accuracy and within-run and between-run precision were in the range of - 2.29 to 2.72 (as one value is in negative side). and 4.65-9.82%, respectively for enasidenib; 0.19-10.3 and 3.22-9.22%, respectively for AGI-16903. Both enasidenib and AGI-16903 were found to be stable in stability (up to three freeze-thaw cycles and for long-term at -80°C for 30 days) and processed (bench-top for 6 h and in in-injector for 24 h) samples. Application of the validated method was shown in a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/farmacocinética , Antineoplásicos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazinas/farmacocinética , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/isolamento & purificação , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Camundongos , Modelos Animais , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/normas , Triazinas/administração & dosagem , Triazinas/isolamento & purificação
9.
J Pharmacol Exp Ther ; 371(3): 692-702, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31578257

RESUMO

In our drug discovery program, we identified a novel orally available and brain-penetrant phosphodiesterase (PDE) 1 inhibitor, 3-methyl-7-(tetrahydro-2H-pyran-4-yl)-2-{[trans-4-(trifluoromethyl)cyclohexyl]-methoxy}imidazo[5,1-f][1,2,4]triazin-4(3H)-one (DSR-141562). In the present study, we characterized the preclinical profile of DSR-141562. This compound has preferential selectivity for predominantly brain-expressed PDE1B over other PDE1 family members, and high selectivity for the PDE1 family over other PDE families and 65 other tested biologic targets. Oral administration of DSR-141562 at 10 mg/kg slightly elevated the cGMP concentration, and it potently enhanced the increase of cGMP induced by a dopamine D1 receptor agonist in mouse brains. The cGMP level in monkey cerebrospinal fluid was also elevated after treatment with DSR-141562 at 30 and 100 mg/kg and could be used as a translational biomarker. Since PDE1B is believed to regulate dopaminergic and glutamatergic signal transduction, we evaluated the effects of this compound using schizophrenia-related behavioral assays. DSR-141562 at 3-30 mg/kg potently inhibited methamphetamine-induced locomotor hyperactivity in rats, while it had only minimal effects on the spontaneous locomotor activity. Furthermore, DSR-141562 at 1-100 mg/kg did not induce any signs of catalepsy in rats. DSR-141562 at 0.3-3 mg/kg reversed social interaction and novel object recognition deficits induced by repeated treatment with an N-methyl-D-aspartate receptor antagonist, phencyclidine, in mice and rats, respectively. In common marmosets, DSR-141562 at 3 and 30 mg/kg improved the performance in object retrieval with detour tasks. These results suggest that DSR-141562 is a therapeutic candidate for positive, negative, and cognitive symptoms in schizophrenia. SIGNIFICANCE STATEMENT: This is the first paper showing that a phosphodiesterase 1 inhibitor is efficacious in animal models for positive and negative symptoms associated with schizophrenia. Furthermore, we demonstrated that this compound improved cognitive function in the common marmoset, a nonhuman primate.


Assuntos
Cognição/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Imidazóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Esquizofrenia/tratamento farmacológico , Triazinas/farmacologia , Animais , Callithrix , GMP Cíclico/análise , GMP Cíclico/líquido cefalorraquidiano , Modelos Animais de Doenças , Feminino , Imidazóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Ratos Long-Evans , Receptores de Dopamina D1/fisiologia , Triazinas/farmacocinética
10.
Anal Chem ; 91(21): 13874-13882, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31584812

RESUMO

This work represents the first reporting of a comprehensive bioanalytical GLP methodology detailing the mass spectrometric quantitation of PF-05212384 dosed as a targeted polymeric encapsulated nanoparticle (PF-07034663) to monkeys. Polymeric nanoparticles are a type of drug formulation that enables the sustained release of an active therapeutic agent (payload) for targeted delivery to specific sites of action such as cancer cells. Through the careful design and engineering of the nanoparticle formulation, it is possible to improve the biodistribution and safety of a given therapeutic payload in circulation. However, the bioanalysis of nanoparticles is challenging due to the complexity of the nanoparticle drug formulation itself and the number of pharmacokinetic end points needed to characterize the in vivo exposure of the nanoparticles. Gedatolisib, also known as PF-05212384, was reformulated as an encapsulated targeted polymeric nanoparticle. The bioanalytical assays were validated to quantitate both total and released PF-05212384 derived from the encapsulated nanoparticle (PF-07034663). Assay performance calculated from quality control samples in three batch runs demonstrated intraday precision and accuracy within 10.3 and 12.2%, respectively, and interday precision and accuracy within 9.1 and 8.5%, respectively. This method leveraged automation to ease the burden of a laborious and complicated sample pretreatment and extraction procedure. The automated method was used to support a preclinical safety study in monkeys in which both released and total PF-05212384 concentrations were determined in over 1600 monkey plasma study samples via LC-MS/MS.


Assuntos
Morfolinas/administração & dosagem , Nanopartículas/análise , Polímeros/química , Triazinas/administração & dosagem , Animais , Cromatografia Líquida/métodos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Haplorrinos , Humanos , Morfolinas/farmacocinética , Nanopartículas/química , Nanopartículas/uso terapêutico , Polímeros/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual , Triazinas/farmacocinética
11.
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
12.
J Med Chem ; 62(16): 7557-7574, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31298539

RESUMO

G protein-coupled receptor 68 (GPR68) is an understudied orphan G protein-coupled receptor (GPCR). It is expressed most abundantly in the brain, potentially playing important roles in learning and memory. Pharmacological studies with GPR68 have been hindered by lack of chemical tools that can selectively modulate its activity. We previously reported the first small-molecule positive allosteric modulator (PAM), ogerin (1), and showed that 1 can potentiate proton activity at the GPR68-Gs pathway. Here, we report the first comprehensive structure-activity relationship (SAR) study on the scaffold of 1. Our lead compound resulted from this study, MS48107 (71), displayed 33-fold increased allosteric activity compared to 1. Compound 71 demonstrated high selectivity over closely related proton GPCRs and 48 common drug targets, and was bioavailable and brain-penetrant in mice. Thus, our SAR study has resulted in an improved GPR68 PAM for investigating the physiological and pathophysiological roles of GPR68 in vitro and in vivo.


Assuntos
Regulação Alostérica , Álcoois Benzílicos/farmacologia , Desenho de Fármacos , Prótons , Receptores Acoplados a Proteínas-G/metabolismo , Triazinas/farmacologia , Animais , Álcoois Benzílicos/síntese química , Álcoois Benzílicos/farmacocinética , Barreira Hematoencefálica/metabolismo , Cálcio/metabolismo , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , Ensaio Radioligante , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacocinética
13.
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
14.
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
15.
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
16.
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
17.
Clin Cancer Res ; 25(16): 4924-4932, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30952639

RESUMO

PURPOSE: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). PATIENTS AND METHODS: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. RESULTS: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. CONCLUSIONS: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazinas/uso terapêutico , Triazinas/uso terapêutico , Biomarcadores Tumorais , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Terapia de Alvo Molecular , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/etiologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/farmacocinética , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Triazinas/farmacocinética
18.
J Pharm Sci ; 108(9): 3112-3117, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30998942

RESUMO

Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight-based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.


Assuntos
Antivirais/farmacocinética , Variação Biológica da População/fisiologia , Influenza Humana/tratamento farmacológico , Modelos Biológicos , Oxazinas/farmacocinética , Piridinas/farmacocinética , Tiepinas/farmacocinética , Triazinas/farmacocinética , Adulto , Fatores Etários , Antivirais/administração & dosagem , Teorema de Bayes , Peso Corporal , Criança , Pré-Escolar , Dibenzotiepinas , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Lactente , Influenza Humana/sangue , Japão , Taxa de Depuração Metabólica/fisiologia , Morfolinas , Oxazinas/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Piridinas/administração & dosagem , Piridonas , Tiepinas/administração & dosagem , Triazinas/administração & dosagem
19.
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
20.
Br J Clin Pharmacol ; 85(7): 1454-1463, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845361

RESUMO

AIMS: Vonoprazan, a new class of potassium-competitive proton pump inhibitors has been found to attenuate the antiplatelet function of clopidogrel in a recent clinical study, despite weak in vitro activity against CYP2C19. To elucidate the mechanism of this interaction, the present study investigated the effects of esomeprazole and vonoprazan on the pharmacokinetics of proguanil, a CYP2C19 substrate. METHODS: Seven healthy male volunteers (CYP2C19 extensive metabolizers) received a single oral administration of 100 mg proguanil/250 mg atovaquone (control phase), oral esomeprazole (20 mg) for 5 days followed by proguanil/atovaquone (esomeprazole phase) and oral vonoprazan (20 mg) for 5 days followed by proguanil/atovaquone (vonoprazan phase). Concentrations of proguanil and its metabolite, cycloguanil, in plasma and urine in each phase were determined using liquid chromatography-tandem mass spectrometry. RESULTS: Coadministration with proton pump inhibitors resulted in increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively, significantly reducing their AUC ratio (cycloguanil/proguanil) to 0.317-fold (95% confidence interval [CI] 0.256-0.379) and 0.507-fold (95% CI 0.409-0.605) in esomeprazole phase and vonoprazan phase, respectively. Esomeprazole and vonoprazan also significantly reduced the apparent formation clearance (cumulative amount of cycloguanil in urine divided by AUC of proguanil) to 0.324-fold (95% CI 0.212-0.436) and 0.433-fold (95% CI 0.355-0.511), respectively, without significant changes in renal clearance of proguanil and cycloguanil. CONCLUSIONS: Although further studies are needed, both esomeprazole and vonoprazan potentially inhibit CYP2C19 at clinical doses, suggesting caution in the coadministration of these drugs with CYP2C19 substrates.


Assuntos
Esomeprazol/farmacologia , Proguanil/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Adulto , Área Sob a Curva , Atovaquona/administração & dosagem , Cromatografia Líquida , Citocromo P-450 CYP2C19/metabolismo , Combinação de Medicamentos , Esomeprazol/administração & dosagem , Humanos , Masculino , Proguanil/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Sulfonamidas/administração & dosagem , Espectrometria de Massas em Tandem , Triazinas/farmacocinética , Adulto Jovem
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