RESUMO
Pyrotinib is an irreversible EGFR/HER2 inhibitor that has been approved for the treatment of breast cancer. The aim of this work was to establish a quantification method for the simultaneous determination of pyrotinib and its metabolite pyrotinib-lactam in rat plasma using UPLC-MS/MS. After simple protein precipitation with acetonitrile, the analytes and internal standard (neratinib) were separated on an ACQUITY BEH C18 column (2.1 × 50 mm, 1.7 µm) using a mobile phase of water containing 0.1% formic acid and acetonitrile. The detection was performed using selected reaction monitoring mode with precursor-to-product ion transitions at m/z 583.2 > 138.1 for pyrotinib, m/z 597.2 > 152.1 for pyrotinib-lactam, and m/z 557.2 > 112.1 for internal standard. The assay exhibited excellent linearity in the concentration range of 0.5-1000 ng/mL for pyrotinib and pyrotinib-lactam. The assay met the criteria of the United States Food and Drug Administration-validated bioanalytical methods and was successfully applied to a pharmacokinetic study of pyrotinib and its metabolite for the first time. Our results demonstrated that pyrotinib rapidly converted into pyrotinib-lactam, whose in vivo exposure was 21% that of pyrotinib.
Assuntos
Acrilamidas/sangue , Acrilamidas/farmacocinética , Aminoquinolinas/sangue , Aminoquinolinas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Acrilamidas/química , Acrilamidas/metabolismo , Aminoquinolinas/química , Aminoquinolinas/metabolismo , Animais , Limite de Detecção , Modelos Lineares , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
BACKGROUND AND OBJECTIVE: Puquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients. METHODS: The analytes of human plasma were prepared by liquid-liquid extraction using methyl-t-butyl ether (MTBE). The plasma analytes were separated by HPLC on Thermo ODS Hypersil column (2.1 × 150 mm; 3 µm) at 25 °C with 5 mmol/L ammonium acetate (A)-acetonitrile (B) (30:70, v/v) as the mobile phase. RESULTS: The total run time was 3.5 min and the elution of puquitinib was at 1.38 min. The detection were analyzed by multiple reaction monitoring (MRM) mode with positive-ion electrospray ionization (ESI) interface using the respective [M + H]+ ions: m/z 318.2 â 261.1 for puquitinib and m/z 258.2 â 121.0 for the internal standard (etofesalamide). The optimized method provided a good linear relation over the concentration range of 1.00-500.00 ng/mL (r = 0.9944) for puquitinib. The intra-day and inter-day precision (relative standard deviation [RSD%]) were within 9.83%, and the intra-day and inter-day accuracy ranged from 91.05 to 103.26%. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. The absolute extraction recovery was on an average of 50.43% for puquitinib and 49.3% for internal standard. In addition, the maximum plasma concentration (Cmax) of puquitinib in dosage from 50 to 800 mg/m2 in the human study showed an increased linearly (57.1-1289.2 ng/mL), which displayed that the concentrations had reached effective levels. CONCLUSIONS: The optimized method was successfully applied to the pharmacokinetic profile study in human cancer patient plasma after the oral administration of puquitinib.
Assuntos
Adenina/análogos & derivados , Aminoquinolinas/sangue , Aminoquinolinas/farmacocinética , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Cromatografia Líquida de Alta Pressão , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Adenina/administração & dosagem , Adenina/sangue , Adenina/farmacocinética , Administração Oral , Idoso , Aminoquinolinas/administração & dosagem , Antineoplásicos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/diagnóstico , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/administração & dosagem , Reprodutibilidade dos TestesRESUMO
Neratinib (NER) and pelitinib (PEL) are irreversible tyrosine kinase inhibitors (TKIs) that have been recently employed in cancer treatment. Apigenin (API), among other flavonoids, is known to have antioxidant, anti-proliferative, and carcinogenic effect. API can potentiate the antitumor effect of chemotherapeutic agents and/or alleviate the side effects of many anticancer agents. Since TKIs are mostly metabolized by CYP3A4 enzymes and that API could alter the enzymatic activity, potential drug interactions could be expected following their co-aministration. In the present study, a bioanalytical UPLC-MS/MS method has been developed and validated for the quantification of NER and PEL in rat plasma, using domperidone (DOM) as an internal standard. Sample preparation was carried out using solid phase extraction (SPE) with C18 cartridges with good extraction recovery of not less than 92.42% (NER) and 89.73% (PEL). Chromatographic analysis was performed on a Waters BEH C18 column with a mobile phase composed of acetonitrile and water, (70:30, v/v), each with 0.1% formic acid. Quantitation was performed using multiple reaction monitoring (MRM) of the transitions from protonated precursor ions [M+H]+, at m/z 557.30 (NER), m/z 468.21 (PEL), and at m/z 426.27 (DOM), to selected product ions at m/z 112.05 (NER), m/z 395.22 (PEL), and at m/z 175.18 (DOM). The method was fully validated as per the FDA guidelines over the concentration range of 0.5-200ng/mL with very low lower limit of quantification (LLOQ) of 0.5ng/mL for both NER and PEL. The intra- and inter-day assay precision and accuracy were evaluated for both drugs and the calculated values of percentage relative standards deviations (%RSD) and relative errors (%Er) were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The applicability of the method was extended to study the possibility of drug interactions following the oral co-administration of NER/PEL with API. Thus, this study could be readily applied in therapeutic drug monitoring (TDM) of cancerous patients receiving such drug combinations.
Assuntos
Aminoquinolinas/sangue , Aminoquinolinas/farmacocinética , Compostos de Anilina/sangue , Compostos de Anilina/farmacocinética , Apigenina/sangue , Apigenina/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas/sangue , Quinolinas/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Flavonoides/sangue , Flavonoides/farmacocinética , Limite de Detecção , Masculino , Plasma/química , Ratos , Ratos Wistar , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Pyrotinib is a novel irreversible tyrosine kinase inhibitor developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The results of phase I clinical trial demonstrated that pyrotinib was well tolerated and exhibited potent antitumor activity. As a promising therapeutic agent for HER2-positive breast cancer, it is of great importance to investigate the biotransformation of pyrotinib in humans and identify the major enzymes involved in its metabolism during its early stage of development for safety consideration. For this purpose, a robust analytical method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) was established to characterize the metabolites of pyrotinib in human plasma, feces, and urine, and identify the primary enzymes responsible for its metabolism. As a result, a total of 24 metabolites were identified, including 16 phase I metabolites resulting from dealkylation, oxidation, dehydrogenation, and carbonylation, and 8 phase II metabolites originating from cysteine and N-acetylcysteine conjugation. Pyrotinib was absorbed into blood by 1h, reached its peak level at 4h, and afterwards underwent slow elimination. The principal metabolites detected in humans (M1, M2, and M5) were products resulting from O-depicoline and pyrrolidine lactam formation, whose structures have been confirmed by the synthetic references. In addition, fecal clearance was the major route of excretion for pyrotinib. Further phenotyping experiment proved that CYP3A4 was the most active enzyme responsible for the biotransformation of pyrotinib, implying the vital necessity of the assessment of the potential CYP3A-mediated drug-drug interactions in humans. Taken together, this study provided valuable metabolic data to explicate the dynamic process of pyrotinib in humans, and important reference basis for its safety evaluation and rational clinical application. The results will also benefit the assessment of the contributions to the overall activity or toxicity from the key metabolites.
Assuntos
Acrilamidas/sangue , Acrilamidas/metabolismo , Aminoquinolinas/sangue , Aminoquinolinas/metabolismo , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Acrilamidas/química , Acrilamidas/farmacocinética , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Humanos , Redes e Vias Metabólicas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinéticaRESUMO
BACKGROUND: The Toll-like receptor 7 (TLR7) activator imiquimod (IMQ) is safe and effective in treating actinic keratosis; however, an intermittent treatment regimen is necessary because of excessive local reactions. OBJECTIVES: To evaluate in vitro potency, pharmacodynamics/pharmacokinetics, toxicity and efficacy in vivo of the newly developed TLR7 ligand-phospholipid conjugate, TMX-202, in a gel formulation. MATERIAL AND METHODS: The effects of TMX-202 were assessed both in vitro on a murine macrophage cell line and in primary bone marrow-derived dendritic cells and in vivo on mice (C57BL/6-wild type, Myd88(-/-) and Tlr7(-/-)). RESULTS: TMX-202 was more potent than IMQ in vitro using murine and human cells. In contrast, in vivo it showed less systemic pro-inflammatory activity and better safety than IMQ. Moreover, the TMX-202 gel formulation exhibited at least comparable efficacy to Aldara in a mouse model for skin proliferative diseases. CONCLUSION: TMX-202 is safe and efficacious without causing excessive adverse effects, suggesting that it may be an alternative to Aldara for the treatment of proliferative skin conditions.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Glicerofosfolipídeos/farmacologia , Glicerofosfolipídeos/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Glicoproteínas de Membrana/genética , Receptor 7 Toll-Like/genética , Adenina/sangue , Adenina/farmacologia , Adenina/uso terapêutico , Aminoquinolinas/sangue , Aminoquinolinas/farmacologia , Animais , Antineoplásicos/sangue , Linhagem Celular , Fatores Quimiotáticos/sangue , Células Dendríticas/fisiologia , Géis/farmacologia , Géis/uso terapêutico , Glicerofosfolipídeos/sangue , Humanos , Imiquimode , Interferon gama/metabolismo , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Queratinócitos/fisiologia , Ceratose Actínica/genética , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/fisiologia , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A bioanalytical liquid chromatography-tandem mass spectrometry assay for the tyrosine kinase inhibitor pelitinib was developed and validated in plasma. Acetonitrile containing the internal standard erlotinib was used to precipitate proteins. The extract was diluted with water and then directly injected onto the sub-2µm particle, bridged ethylsilica hybrid trifunctional bonded C18 column. A gradient consisting of 0.02% (v/v) formic acid in a methanol-water mixture was used. The ionization mode of the electrospray interface was positive and the analyte was detected by a triple quadrupole mass spectrometer in the selected reaction monitoring mode. The calibration range of the assay was 1-200ng/ml. The within day precision, the between day precision, and the accuracy were 3.5-7.4%, 4.5-8.6%, and 94.0-104.8%, respectively. The stability of the drug was sufficient under all relevant conditions. The validated assay was used to measure drug levels in wild-type FVB mice and pharmacokinetic parameters were assessed.
Assuntos
Aminoquinolinas/sangue , Compostos de Anilina/sangue , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/sangue , Aminoquinolinas/farmacocinética , Compostos de Anilina/farmacocinética , Animais , Estabilidade de Medicamentos , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em TandemRESUMO
Imiquimod 3.75% cream is a topical formulation of imiquimod intended for daily application to treat actinic keratoses of the entire face or balding scalp. The objective of the study was to characterize serum imiquimod and metabolite pharmacokinetics. Nineteen subjects with actinic keratoses applied two packets of imiquimod 3.75% cream (18.75 mg imiquimod total) once daily for 21 days to a treatment area approximately 200 cm(2) in size on the face and/or balding scalp. Blood samples were obtained prior to application of doses 1, 7, 14 and 21, and at selected timepoints after application of doses 1 and 21. After multiple dosing (day 21) serum imiquimod mean C (max) was 0.323 (standard deviation 0.159) ng/mL, mean AUC(0-24) 5.974 (3.088) ng h/mL, and mean T(1/2) 29.3 (17.0) h. Steady-state was achieved by day 14; multiple dose accumulation ratios were 2.8 based on imiquimod C (max) and 3.9 based on AUC. Serum concentrations of imiquimod metabolites were only sporadically quantifiable in three subjects. One subject discontinued from study for adverse events of body aches and fatigue that were attributed to study drug. Treatment-related adverse events occurred in 42.1% (8/19) of the subjects. Systemic imiquimod exposure, as reflected by serum drug concentration, was low after daily application of two packets of imiquimod 3.75% cream for 21 days. Steady state was achieved by day 14, and the observed half-life of approximately 29 h supports daily dosing of the product.
Assuntos
Aminoquinolinas/farmacocinética , Face/patologia , Ceratose Actínica/tratamento farmacológico , Couro Cabeludo/patologia , Pele/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Alopecia , Aminoquinolinas/sangue , Feminino , Meia-Vida , Humanos , Imiquimode , Ceratose Actínica/sangue , Ceratose Actínica/patologia , Ceratose Actínica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pele/metabolismo , Pele/patologiaRESUMO
OBJECTIVES: To explore the efficacy and safety of imiquimod 5% cream as a treatment for infantile hemangioma. DESIGN: Phase II, open-label, noncomparative study of imiquimod applied during 16 weeks, with posttherapy follow-up 16 weeks later (8 months total). SETTING: Outpatient pediatric tertiary care referral center in Quebec, Canada. PARTICIPANTS: Healthy infants up to 8.8 months of age with previously untreated, nonulcerated, proliferative superficial or mixed infantile hemangioma, excluding periorbital, or perineal localization, > or =100 cm2 in size. INTERVENTION: Topical imiquimod applied three to seven times per week for 16 weeks to infantile hemangioma. MAIN OUTCOME MEASURES: Lesion area, volume, depth (Doppler ultrasound), and color (erythema), serum drug, and interferon-alpha levels. RESULTS: Sixteen infants (11 girls, 5 boys) with a mean age at entry of 4.1 months and mean lesion area of 32.89 cm2, and volume of 39.98 cm3 were enrolled. Two participants discontinued treatment early, one for an adverse event (crying upon application), the other because of the lack of compliance. Local skin reactions were consistent with those reported in adults. Two cases had a decrease and three had an increase in lesion parameters; otherwise no meaningful changes in lesion area, volume, or depth were observed. At the 4-month posttreatment visit, 11 of 14 subjects had improvement in erythema (marginal homogeneity test = 2.668, p = 0.008). Measured serum drug and interferon-alpha levels were low or undetectable. CONCLUSIONS: Treatment of infants with infantile hemangioma with imiquimod up to seven times per week for 16 weeks was generally well tolerated with low systemic exposure. Improvement was observed in hemangioma coloration, but not lesion size, suggesting effects were limited to the superficial component.
Assuntos
Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Hemangioma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Tópica , Aminoquinolinas/sangue , Antineoplásicos/sangue , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Imiquimode , Lactente , Interferon-alfa/sangue , Masculino , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/urinaRESUMO
Nanoparticles have widely been studied in drug delivery research for targeting and controlled release. The aim of this article is application of nanoparticles as an inhalable agent for treatment of lung cancer. To deposit effectively deep the particles in the lungs, the PLGA nanoparticles loaded with the anticancer drug 6-{[2-(dimethylamino)ethyl]amino}-3-hydroxyl-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103) were prepared in the form of nanocomposite particles. The nanocomposite particles consist of the complex of drug-loaded nanoparticles and excipients. In this study, the anticancer effects of the nanocomposite particles against the lung cancer cell line A549. Also, the concentration of TAS-103 in blood and lungs were determined after administration of the nanocomposite particles by inhalation to rats. TAS-103-loaded PLGA nanoparticles were prepared with 5% and 10% of loading ratio by spray drying method with trehalose as an excipient. The 5% drug-loaded nanocomposite particles were more suitable for inhalable agent because of the sustained release of TAS-103 and higher FPF value. Cytotoxicity of nanocomposite particles against A549 cells was higher than that of free drug. When the nanocomposite particles were administered in rats by inhalation, drug concentration in lung was much higher than that in plasma. Furthermore, drug concentration in lungs administered by inhalation of nanocomposite particles was much higher than that after intravenous administration of free drug. From these results, the nanocomposite particle systems could be promising for treatment of lung cancer.
Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Nanocompostos/administração & dosagem , Nanocompostos/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Administração por Inalação , Aminoquinolinas/administração & dosagem , Aminoquinolinas/sangue , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Indenos/administração & dosagem , Indenos/sangue , Indenos/farmacologia , Indenos/uso terapêutico , Ácido Láctico/química , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Tamanho da Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-DawleyRESUMO
We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai-Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine (400 mg daily for 3 days), followed by tafenoquine monthly (400 mg every 4 weeks) for 5 months. Consecutive monthly mean (+/- standard deviation) trough plasma tafenoquine concentrations were 223+/-41, 127+/-29, 157+/-51, 120+/-24, and 88+/-20 ng/mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/mL, which was approximately 3-fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.
Assuntos
Aminoquinolinas/sangue , Antimaláricos/sangue , Adulto , Artemisininas/sangue , Artesunato , Quimioprevenção , Método Duplo-Cego , Doxiciclina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Militares , Sesquiterpenos/sangue , TailândiaRESUMO
A simple and rapid method for the analysis of a novel anticancer drug, TAS-103, and its metabolite demethyl-TAS-103 in monkey plasma has been developed. This method is based on high-performance liquid chromatography with visible detection at 460 nm after solid-phase extraction with a Sep-Pak Vac PS-2 cartridge. The extraction recoveries of each compound, including the internal standard TAS-1-1018, were from 88 to 102%. The quantitation limit of each compound was 5.0 ng/ml in 0.5 ml of plasma. The coefficients of variation for each compound ranged from 0.9 to 4.9%, and relative errors for each compound ranged from -3.8 to 4.6%. Both compounds in monkey plasma were stable at -80 degrees C for 39 days and the extracts were stable at ambient temperature for 24 h. This method has been demonstrated to be useful for the pharmacokinetic study of TAS-103 in monkey plasma after intravenous administration.
Assuntos
Aminoquinolinas/sangue , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Indenos/sangue , Aminoquinolinas/farmacocinética , Animais , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Indenos/farmacocinética , Macaca fascicularis , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Cytochalasin B alone induces little superoxide production in intact rabbit peritoneal neutrophils. The cytochalasin causes a strong production of superoxide in cells treated with membrane-permeabilizing polycations. Several polycations were able to express the activating effect of cytochalasin B. Especially the poly-L-arginine with a molecular weight of 24,000 proved to be effective. The effectiveness of some polycations is limited because they inactivate the superoxide-generating oxidase system of the neutrophil. Cytochalasin B-induced superoxide production starts at poly-L-arginine concentrations that cause a change of membrane permeability. At the concentrations of cytochalasin B used in our experiments, the binding of [3H]cytochalasin B is not enhanced in poly-L-arginine-treated cells as compared with control cells. Activation of superoxide production by cytochalasin B in polycation-treated neutrophils occurs both in the presence or absence of extracellular Ca2+. When the cells are pretreated with agents that known to interfere with intracellular Ca2+, the subsequent activation is strongly inhibited, suggesting a role for intracellular Ca2+ in cytochalasin B-induced activation. It is suggested that cytochalasin B alone is not able to activate all the steps that eventually result in complete activation of the superoxide-generating oxidase and that membrane perturbation by polycation provides activation of the remaining steps.
Assuntos
Citocalasina B/farmacologia , Neutrófilos/efeitos dos fármacos , Poliaminas , Polímeros/farmacologia , Superóxidos/metabolismo , Sequência de Aminoácidos , Aminoquinolinas/sangue , Animais , Cálcio/fisiologia , Citocalasina B/metabolismo , Corantes Fluorescentes , L-Lactato Desidrogenase/sangue , Dados de Sequência Molecular , Neutrófilos/metabolismo , Peptídeos/farmacologia , Polieletrólitos , Coelhos , Ensaio Radioligante , Explosão Respiratória/efeitos dos fármacos , Espectrometria de FluorescênciaRESUMO
Acodazole (NSC 305884) is a synthetic imidazoquinoline which has antimicrobial as well as antineoplastic properties. A Phase I trial of acodazole administered as a 1-h i.v. infusion once weekly X 4 was conducted. Mild to moderate nausea and vomiting and moderate burning and erythema at the infusion site were the only toxicities seen among 33 patients treated over 51 courses at doses between 20 mg/m2/week and 888 mg/m2. The first patient treated at 1184 mg/m2 developed an irregular pulse and was found to have a prolonged cardiac output interval (Q-Ti) on electrocardiogram and polymorphic ventricular tachycardia ("torsades des pointes"). Careful study of five additional patients treated according to a modified schedule (340 mg/m2 week one, 500 mg/m2 week 2, 666 mg/m2 week 3, and 888 mg/m2 week 4) revealed 20% or greater Q-Ti prolongation after 20 of 27 treatments; Q-Ti prolongation had resolved 24-36 h after each infusion. Q-Ti prolongation occurred at all dose levels; no ventricular arrhythmias occurred. Acodazole was cleared with a long t1/2 (20.7 h) primarily by nonrenal mechanisms. No alterations in peak plasma levels or excretion were seen in the patients in whom Q-Ti prolongation was detected. No antitumor activity was seen. Further development of acodazole will require delineation of pharmacological means of surppressing this Q-Ti prolongation.
Assuntos
Aminoquinolinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Coração/efeitos dos fármacos , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Aminoquinolinas/efeitos adversos , Aminoquinolinas/sangue , Antibióticos Antineoplásicos/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Avaliação de Medicamentos , Eletrocardiografia , Eletrofisiologia , Feminino , Coração/fisiologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/sangue , Cinética , Síndrome do QT Longo/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/tratamento farmacológicoRESUMO
Specific and sensitive analytical methods have been developed for the measurement of antrafenine and its main acid metabolite, 2-([17-(trifluoromethyl)-4-quinolinyl] amino) benzoic acid (FQB), at therapeutic concentrations in plasma and urine. Following the addition of internal standards (the methyl ester of FQB and 2-([8-(trifluoromethyl)-4-quinolinyl] amino) benzoic acid) the parent drug and the metabolite were extracted from biological material with diethyl ether at a weakly acid pH. Drug extracts were evaporated to dryness prior to chromatographic analysis. Antrafenine was measured by high-performance liquid chromatography using a Spherisorb 5-micrometer ODS column with acetonitrile-0.1 M sodium acetate as the mobile phase. Samples were injected automatically using a 500-microliter injection loop. The detector wavelength was 353 nm corresponding to the maximum UV absorption of both drug and internal standard. The coefficient of variation (C.V.) for the determination of antrafenine concentrations between 5 and 250 ng/ml ranged between 24 and 3%, respectively. The acid metabolite of antrafenine was measured by gas-liquid chromatography with electron-capture detection using a 1 m column packed with 3% OV-225 on Gas-Chrom Q (100-120 mesh) at 240 degrees C and on-column methylation with trimethylphenyl ammonium hydroxide. The C. V. of the method for the analysis of metabolite concentrations between 10 and 500 ng/ml ranged between 3 and 9%, respectively.
Assuntos
Aminoquinolinas/sangue , Piperazinas/sangue , Aminoquinolinas/administração & dosagem , Aminoquinolinas/urina , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Piperazinas/administração & dosagem , Piperazinas/urinaRESUMO
Several substituted 8-aminoquinolines related to known antimalarial drugs have been studied by gas chromatography mass spectrometry. 5,6-Dihydroxy-8-aminoquinoline, a possible metabolite of Primaquine, can be detected by single ion monitoring after conversion to a trimethylsilyl ether derivative. The mass spectra obtained in this study indicate that there are certain ions which are characteristic of the trimethylsilyl ethers of hydroxylated 8-aminoquinolines and 5,6-dimethoxy-8-aminoquinolines. These compounds should thus be amenable to analysis if they were produced during in vivo metabolism studies. Using selected ion monitoring the derivatized compounds can be detected at submicrogram levels.