RESUMO
High-dose methotrexate (HDMTX) is a central component in the treatment of acute lymphoblastic leukemia, osteosarcoma, and some lymphomas and brain tumors. MTX is given at lethal doses and then is followed by rescue treatment with folinic acid (FA). Despite FA rescue, many patients suffer severe toxicity. The pharmacokinetics of FA rescue have not been sufficiently studied. However, optimization of FA rescue could potentially increase anti-tumor effects, whilst decreasing organ toxicity. Here, we describe our efforts to establish and optimize a liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the simultaneous determination of five essential components of the folate cycle, as well as MTX and its two metabolites. The method was applied to 6 individual patients receiving HDMTX, with 3 or 4 measurements for each patient. The method allows analysis of samples that were initially frozen. This notion, together with the test results in the 6 pilot patients, shows the feasibility of this method to study MTX and FA pharmacokinetics during HDMTX treatment. The method has the potential to optimize HDMTX and FA rescue treatment in individual patients.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Cromatografia Líquida/métodos , Ácido Fólico/sangue , Metotrexato/administração & dosagem , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Relação Dose-Resposta a Droga , Ácido Fólico/administração & dosagem , Humanos , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangueRESUMO
PURPOSE: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS). RESULTS: The median sorafenib concentration was 2.91 µg/mL (range 0.74-8.8 µg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 µg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 µg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 µg/mL and ≥ 3.45 µg/mL [median 17.8 months (1.40-3.45 µg/mL) vs. 5.3 months (< 1.40 µg/mL) and 9.5 months (≥ 3.45 µg/mL)]. CONCLUSIONS: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 µg/mL in patients with HCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sorafenibe/efeitos adversos , Sorafenibe/sangue , Sorafenibe/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). METHODS: Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. RESULTS: A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. CONCLUSION: The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Capecitabina/administração & dosagem , Capecitabina/farmacologia , Cronofarmacoterapia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Capecitabina/efeitos adversos , Capecitabina/sangue , Ritmo Circadiano , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Timidilato Sintase/metabolismo , Uridina Trifosfato/análogos & derivados , Uridina Trifosfato/sangueRESUMO
Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.
Assuntos
Alcaloides/química , Alcaloides/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacocinética , Isoflavonas/química , Isoflavonas/farmacocinética , Alcaloides/sangue , Animais , Antineoplásicos/sangue , Azocinas/sangue , Azocinas/química , Azocinas/farmacocinética , Feminino , Isoflavonas/sangue , Fígado/metabolismo , Simulação de Acoplamento Molecular , Quinolizinas/sangue , Quinolizinas/química , Quinolizinas/farmacocinética , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build-up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapse-free and overall survival. The CXCR4 ligand, CXCL12 (SDF-1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a 'multi-hit' therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in pre-clinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a 'multi-hit' therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM.
Assuntos
Quimiocina CXCL12/fisiologia , Leucemia Mieloide Aguda/metabolismo , Proteínas de Neoplasias/fisiologia , Receptores CXCR4/fisiologia , Transdução de Sinais/fisiologia , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/sangue , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzilaminas , Medula Óssea/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Hipóxia Celular , Movimento Celular/fisiologia , Micropartículas Derivadas de Células , Ensaios Clínicos como Assunto , Ciclamos , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/fisiologia , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Peptídeos/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Piridinas/uso terapêutico , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente TumoralAssuntos
Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/farmacocinética , Antineoplásicos/sangue , Povo Asiático , Monitoramento de Medicamentos , Humanos , Índia , Valores de Referência , Sorafenibe/sangue , Sorafenibe/uso terapêuticoRESUMO
PURPOSE: Over the past 30 years, no consistent survival benefits have been recorded for anticancer agents of advanced hepatocellular carcinoma (HCC), except for the multikinase inhibitor sorafenib (Nexavar®), which clinically achieves only ~3 months overall survival benefit. This modest benefit is attributed to limited aqueous solubility, slow dissolution rate and, consequently, limited absorption from the gastrointestinal tract. Thus, novel formulation modalities are in demand to improve the bioavailability of the drug to attack HCC in a more efficient manner. In the current study, we aimed to design a novel sorafenib-loaded carbon nanotubes (CNTs) formula that is able to improve the therapeutic efficacy of carried cargo against HCC and subsequently investigate the antitumour activity of this formula. MATERIALS AND METHODS: Sorafenib was loaded on functionalized CNTs through physical adsorption, and an alginate-based method was subsequently applied to microcapsulate the drug-loaded CNTs (CNTs-SFN). The therapeutic efficacy of the new formula was estimated and compared to that of conventional sorafenib, both in vitro (against HepG2 cells) and in vivo (in a DENA-induced HCC rat model). RESULTS: The in vitro MTT anti-proliferative assay revealed that the drug-loaded CNTs formula was at least two-fold more cytotoxic towards HepG2 cells than was sorafenib itself. Moreover, the in vivo animal experiments proved that our innovative formula was superior to conventional sorafenib at all assessed end points. Circulating AFP-L3% was significantly decreased in the CNTs-SFN-MCs-treated group (14.0%) in comparison to that of the DENA (40.3%) and sorafenib (38.8%) groups. This superiority was further confirmed by Western blot analysis and immunofluorescence assessment of some HCC-relevant biomarkers. CONCLUSION: Our results firmly suggest the distinctive cancer-suppressive nature of CNTs-SFN-MCs, both against HepG2 cells in vitro and in a DENA-induced HCC rat model in vivo, with a preferential superiority over conventional sorafenib.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Desenho de Fármacos , Neoplasias Hepáticas/tratamento farmacológico , Nanotubos de Carbono/química , Sorafenibe/uso terapêutico , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Peso Corporal/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Nanotubos de Carbono/ultraestrutura , Niacinamida/farmacologia , Ratos Wistar , Sorafenibe/sangue , Sorafenibe/farmacocinética , Sorafenibe/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade EstáticaRESUMO
Objective: To explore the features of imatinib mesylate (IM) plasma concentration during adjuvant therapy and clinical factors associated with IM plasma concentration in patients with high risk gastrointestinal stromal tumors (GIST), and to determine whether IM plasma concentration <1100 µg/L influences the efficacy of adjuvant therapy. Methods: A retrospective case control study method was used. Case inclusion criteria: (1) complete resection of lesion and GIST confirmed by pathology; (2) high risk classified according to modified National Institutes of Health classification system (2008); (3) administration of IM 400 mg/d for at least 1 month; (4) not taking the medication likely affecting IM pharmacokinetic, such as rifampicin, dilantin, and carbamazepine, within 1 month before blood collection. Data of GIST patients who visited GIST Disease - Oriented Outpatient, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 to December 2018 were retrospectively analyzed. After taking IM for 22-26 hours, 5 ml of peripheral venous blood was collected into EDTA anticoagulant tube. IM plasma concentration was detected by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Patients were divided into <1100 µg/L group and ≥1100 µg/L group according to plasma concentration. Linear regression was used to analyze the relevance between clinical features and IM plasma concentration. Parameters with normal distribution were analyzed by Pearson correlation coefficient, and parameters with non-normal distribution were analyzed by Spearman correlation. Kaplan-Meier survival curves and COX regression model were used for survival analysis. Results: Among the 85 patients enrolled in the study, 49 patients (57.6%) were male and 36 (42.4%) were female, with mean age of (51.9±11.0) years. The body mass index was (22.5±2.9) kg/m(2) and body surface area was (1.6±0.2) m(2). Thirty patients received gene test, including 23 patients with c-Kit exon 11 mutation, 4 with c-Kit exon 9 mutation, 1 with c-Kit exon 11 and 17 mutation and 2 without c-Kit or PDGFRA gene mutation. The mean IM plasma concentration was (1391.4±631.3) µg/L, and there were 32 patients with plasma concentration <1100 µg/L and 53 patients with plasma concentration ≥1100 µg/L. There were no statistically significant differences between the two groups in gender, age, body mass index, body surface area, hematological examination (white blood cells, albumin, alanine aminotransferase, aspartate aminotransferase and serum creatinine), tumor location, tumor size, mitotic counts, duration of adjuvant therapy and methods of operation (all P>0.05). Positive correlation between IM plasma concentration and serum creatinine was observed in linear regression analysis (r=0.297, P=0.007), but there were no correlations between IM plasma concentration and age (r=0.044, P=0.686), body mass index (r=0.066, P=0.547), body surface area (r=-0.010, P=0.924), white blood cells (r=-0.080, P=0.478), albumin (r=-0.065, P=0.563), alanine aminotransferase (r=0.114, P=0.308), aspartate aminotransferase (r=0.170, P=0.127) and duration of adjuvant therapy (ρ=0.060, P=0.586). There was no statistically significant difference in IM plasma concentration between patients with different genders (t=0.336, P=0.738) and patients with different surgical methods (F=0.888, P=0.451). Up to March 1, 2019. the median follow-up time was 30 (range 4-49) months. Tumor recurrence was detected in two patients with plasma concentration <1100 µg/L and two with plasma concentration ≥1100 µg/L. One recurrent patient with plasma concentration <1100 µg/L was detected to harbor c-Kit exon 11 and exon 17 mutations, and the other did not receive gene detection. Two recurrent patients with plasma concentration ≥1100 µg/L were both detected to harbor c-Kit exon 9 mutation. The 3-year relapse-free survival rate was 96.4% in the cohort, 96.2% in patients with plasma concentration <1100 µg/L, and 96.6% in patients with plasma concentration ≥1100 µg/L. No significant difference in relapse-free survival was observed between the two groups (P=0.204). Univariate Cox analysis showed that IM plasma concentration <1100 µg/L was not a risk factor for patients with high risk GIST (HR=0.238, 95% CI: 0.022-2.637, P=0.242). Conclusions: IM plasma concentration of adjuvant therapy in patients with high risk GIST varies with individual. Patients with higher level of serum creatinine are more likely to have a higher plasma concentration. A blood drug concentration standard of less than 1100 µg/L for advanced GIST patients may not influence the prognosis of patients with high risk GIST.
Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Fatores de Risco , Espectrometria de Massas em TandemRESUMO
Gynura procumbens (Lour.) Merr. is an evergreen edible vine in southern China. The antioxidant activity and metabolites of chlorogenic acid dimer from Gynura procumbens (Lour.) Merr. were evaluated by the model of in vitro digestion and in vivo metabolomics approach, respectively. Moreover, metabolites of chlorogenic acid dimer in blood and urine of Sprague-Dawley rats were determined by HPLC-ESI-QTOF-MS/MS. In vitro digestion results suggested the antioxidant activity of the purified chlorogenic acid dimer was significantly enhanced after simulated digestion. Meanwhile, in vivo metabolism results showed that 7 and 20 new metabolites were observed in blood and urine, respectively, suggesting that hydrolysis along with methylation, glucuronidation and other reactions may all happen when the chlorogenic acid dimer entered the digestive and metabolic systems, which inducing and exhibiting various biological activities through metabolism. PRACTICAL APPLICATIONS: Gynura procumbens (Lour.) Merr. (GPM) is an evergreen edible vine with the effects of anticancer, anti-inflammatory, antiviral, depressurization, and antioxidation. As a health care vegetable, it is not usually eaten in daily life. Our current study shows that chlorogenic acid dimer extracted from GPM has a significant enhanced antioxidant ability after gastro-intestinal digestion in vitro, and their metabolites in vivo of urine is far more than that of blood, which may indicate that the chlorogenic acid dimer can be fully absorbed and decomposed through the gastro-intestinal digestion and metabolism. Thus, GPM could be used as a functional food ingredient for antioxidant enhancement to promote the economic value. The research also provides theoretical data for the intensive processing and utilization of GPM, as well as for the relative research on digestion and metabolism of edible plants.
Assuntos
Ácido Clorogênico , Digestão/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/metabolismo , Plantas Medicinais/metabolismo , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/urina , Antineoplásicos/sangue , Antineoplásicos/urina , Antioxidantes/metabolismo , Asteraceae/metabolismo , China , Ácido Clorogênico/isolamento & purificação , Ácido Clorogênico/metabolismo , Cromatografia Líquida de Alta Pressão , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: Evidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreductive surgery (MI-SCS). METHODS: Cisplatin levels were assessed at 0, 20, 40, 60, and 120 minutes in: 1) blood samples, 2) peritoneal perfusate, and 3) peritoneal biopsies at the end of HIPEC. Median Cmax has been used to identify women with high and low drug levels. Progression-free survival (PFS) was calculated as the time elapsed between SCS+HIPEC and secondary recurrence or last follow-up visit. RESULTS: Nine (45.0%) women received MI-SCS, and 11 (55.0%) O-SCS. At 60 minutes, median cisplatin Cmax in peritoneal tissue was higher in patients treated with MI-SCS compared to O-SCS (Cmax=8.262 µg/mL vs. Cmax=4.057 µg/mL). Furthermore, median cisplatin plasma Cmax was higher in patients treated with MI-SCS compared to O-SCS (Cmax=0.511 vs. Cmax=0.254 µg/mL; p-value=0.012) at 120 minutes. With a median follow-up time of 24 months, women with higher cisplatin peritoneal Cmax showed a longer PFS compared to women with low cisplatin peritoneal levels (2-years PFS=70% vs. 35%; p-value=0.054). CONCLUSIONS: We demonstrate for the first time that minimally invasive route enhances cisplatin peritoneal tissue uptake during HIPEC, further evaluations are needed to confirm the correlation between peritoneal cisplatin levels after HIPEC and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01539785.
Assuntos
Antineoplásicos/farmacocinética , Carcinoma Epitelial do Ovário/terapia , Cisplatino/farmacocinética , Hipertermia Induzida/métodos , Neoplasias Ovarianas/terapia , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Carcinoma Epitelial do Ovário/patologia , Cisplatino/administração & dosagem , Cisplatino/sangue , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Estudos ProspectivosRESUMO
Sunitinib is a multi-targeted tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor and is currently being investigated against other forms of malignant tumors. Recently great interest has emerged for the application of sunitinib to glioblastoma treatment. In order to have a method with broad applicability it will be of importance to have access to a method that could be applied both in human plasma and cell uptake studies. No method has been reported thus far for the estimation of sunitinib uptake in glioma cells. We therefore set out to develop a method that could be applied for quantifying sunitinib in human plasma and in cell uptake studies. The method was validated and accredited according to ISO 17025:2005 guideline in human plasma and successfully applied to cancer patient plasma. Also, the method was effectively recruited to establish a protocol for the evaluation of sunitinib accumulation into M095K glioma cells. This method could significantly contribute to developmental phases in repurposing this drug in different cancer types.
Assuntos
Antineoplásicos/análise , Carcinoma de Células Renais/sangue , Avaliação Pré-Clínica de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Neoplasias Renais/sangue , Inibidores de Proteínas Quinases/análise , Sunitinibe/análise , Administração Oral , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Reposicionamento de Medicamentos , Voluntários Saudáveis , Humanos , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Sunitinibe/sangue , Sunitinibe/uso terapêutico , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodosRESUMO
For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.
Assuntos
Antineoplásicos/farmacocinética , Bexaroteno/farmacocinética , Portadores de Fármacos/metabolismo , Ácido Linoleico/metabolismo , Óleo de Girassol/metabolismo , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Bexaroteno/administração & dosagem , Bexaroteno/sangue , Disponibilidade Biológica , Lipólise , Masculino , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
Nimbolide is a novel, natural compound with promising potential as a drug candidate for anticancer activity. It is isolated from the Indian traditional medicinal plant Azadirachta indica popularly known as neem. The present study was undertaken to explore the oral bioavailability and pharmacokinetic characteristics of nimbolide in rats using the LC/QTOF/MS method. A simple protein precipitation method using acetonitrile was employed for extracting nimbolide from rat plasma. The chromatographic separation of nimbolide and the internal standard (regorafenib) was attained on an Aquity BEH C18 column (100â¯×â¯2.1â¯mm, 2.7⯵m), using ACN and 0.1% of formic acid in water as mobile phase components in a gradient elution mode at a flow rate of 0.45â¯mL/min over a short run time of 4â¯min. A mass detection was carried out using target ions of [Mâ¯+â¯H]+ at m/z 467.2074 for nimbolide and m/z 483.0847 for the internal standard. The LC/MS method was validated and all the parameters were found well within the specified limits. The calibration curve was constructed in the range of 1-1000â¯ng/mL. The method shows good accuracy (91.66-97.12%) and precision (intra 2.21-6.92% CV and inter-day 2.56-4.62% CV). This developed LC/MS method was effectively applied to the pharmacokinetic study of nimbolide upon oral and intravenous administration in rats. In concordance with its physicochemical properties and high lipophilicity, we found that it shows poor oral absorption at different doses (10, 30 and 50â¯mg/kg). As expected, higher plasma levels were observed upon intravenous (10â¯mg/kg) administration. This method can be extended for evaluation of drug interaction and drug metabolism in rats as well as in humans. Moreover, our rapid and sensitive method may cater the need to accelerate the preclinical formulation development and lead optimization for future drug development of this potent anticancer agent. Further, our oral bioavailability studies demonstrated that nimbolide possesses poor oral absorption, which could be the probable reason for the delay in therapeutic translation of this promising agent for clinical use.
Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Cromatografia Líquida/métodos , Limoninas/sangue , Limoninas/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Estabilidade de Medicamentos , Limite de Detecção , Limoninas/administração & dosagem , Limoninas/química , Modelos Lineares , Masculino , Espectrometria de Massas/métodos , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Zhuanggu Formula (WSZG) is a traditional Chinese medicine (TCM) prescription used in clinics for adjuvant treatment of breast cancer bone metastases in Longhua Hospital in China. WSZG has been reported to decrease the risk of bone metastases and alleviate the severity of bone lesions in a breast cancer xenograft model. AIM OF THE STUDY: The present study aimed at investigating the pharmacokinetic behaviors of six coumarins in normal and breast cancer bone-metastatic mice following oral administration of WSZG extract. MATERIALS AND METHODS: A bone-metastatic mouse model was established by intracardiac injection of MDA-MB-231BO breast cancer cells, and WSZG extract (1.60â¯g/kg) was given orally to the model and normal mice for 4 weeks. Then, the blood pharmacokinetic parameters of six bioactive components from WSZG (psoralen, isopsoralen, bergapten, xanthotoxin, osthole, and imperatorin) were analyzed by liquid chromatography tandem mass spectrometry. RESULTS: There were significant differences in pharmacokinetic behaviors between normal and pathological states. Compared with normal mice, the model mice showed significantly increased AUC0-t and AUC0-∞ of the bioactive compounds (Pâ¯<â¯0.05) and significantly decreased total blood clearance (CLZ/F) (Pâ¯<â¯0.05). CONCLUSIONS: The different pharmacokinetic behaviors might be partly ascribed to intestinal functional disorders and imbalance of gastrointestinal microbiota under the morbid state. The findings provide some valuable information to evaluate the clinical efficacy and safety of this TCM formula.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias Ósseas/metabolismo , Cumarínicos/farmacocinética , Neoplasias Mamárias Experimentais/metabolismo , Extratos Vegetais/farmacocinética , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/sangue , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Cumarínicos/sangue , Cumarínicos/uso terapêutico , Feminino , Humanos , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Extratos Vegetais/sangue , Extratos Vegetais/uso terapêuticoRESUMO
BACKGROUND: The evaluation of the efficacy and toxicity of hyperthermic intraoperative peritoneal chemotherapy presents some difficulties, due in part to the lack of information about the pharmacokinetic behavior of the drugs administered in this procedure. The aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters. METHODS: Oxaliplatin peritoneal and plasma concentrations from 37 rats treated by either intravenous or intraperitoneal oxaliplatin administrations under different instillation times, temperatures and doses were analyzed according to a population pharmacokinetic approach using the software NONMEM V7.3®. RESULTS: Intraperitoneal (nâ¯=â¯115) and plasma (nâ¯=â¯263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distribution were 3.25â¯mL/min (39.1%), 53.6â¯mL (37.8%) and 54.1â¯mL (77.3%), respectively. Clearance decreased to 0.151â¯mL/min (39.1%) when the instillation was still ongoing, at 31.4â¯min. One of the possible reasons behind the clearance decrease would be an alteration of renal function due to surgery and/or hyperthermia. CONCLUSIONS: This study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters.
Assuntos
Antineoplásicos/farmacocinética , Hipertermia Induzida , Modelos Biológicos , Compostos Organoplatínicos/farmacocinética , Administração Intravenosa , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Terapia Combinada , Injeções Intraperitoneais , Masculino , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/sangue , Oxaliplatina , Peritônio/metabolismo , Ratos WistarRESUMO
BACKGROUND: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. METHODS: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. RESULTS: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. CONCLUSIONS: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Nitrilas/farmacocinética , Tamoxifeno/farmacocinética , Triazóis/farmacocinética , Undaria , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacocinética , Neoplasias da Mama/sangue , Feminino , Interações Ervas-Drogas , Humanos , Letrozol , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/sangue , Fitoterapia , Polissacarídeos/administração & dosagem , Polissacarídeos/efeitos adversos , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/análogos & derivados , Tamoxifeno/sangue , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/sangueRESUMO
OBJECTIVE: To evaluate the feasibility and therapeutic efficacy of transhepatic arterial embolization with superparamagnetic iron oxide (SPIO) and lipiodol (LIP) for the treatment of VX2 tumor in rabbits.â© Methods: Twenty-four rabbits with hepatic VX2 tumors by surgical implantation were randomly divided into 4 groups and treated with transhepatic arterial embolization of 4 different agents as follows (n=6 each): doxorubicin (DOX) group, DOX-LIP group, SPIO-DOX group, and SPIO-DOX-LIP group. Liver function (AST and ALT) was measured at 0, 1, 3, 5 and 7 d after transhepatic arterial embolization. The serum DOX level was measured at 0, 5, 15, 30, 60, and 120 minutes after transhepatic arterial embolization. MRI was performed at 7 d after the treatment to assess the distribution of SPIO in the SPIO-DOX group and SPIO-DOX-LIP group, while CT was performed to assess the distribution of LIP in the DOX-LIP group and SPIO-DOX-LIP group. All the rabbits were sacrificed and their livers were removed at 7 d after treatment for the detection of tissue DOX level. The histopathologic examinations were performed including HE staining, Prussian blue staining and TUNEL assay, and then the tumor necrosis percentage and apoptosis index were calculated.â© Results: Compared to the DOX group, the levels of AST and ALT in other 3 groups were significantly elevated at 1 and 3 d after embolization (P<0.05). The levels of ALT and AST in the DOX group, DOX-LIP group or SPIO-DOX-LIP group returned to the baseline at day 7, there were no significant differences (P>0.05). The SPIO-DOX-LIP group exhibited the lowest serum DOX level at all time points up to 120 minutes after embolization (P<0.05). However, the tissue DOX level in the SPIO-DOX-LIP group was the highest among all groups at day 7 (P<0.05). The SPIO-DOX group and SPIO-DOX-LIP group showed significantly lower MRI signal intensity of tumors in T2 weighted imaging (T2WI) at day 7. Meanwhile DOX-LIP group and SPIO-DOX-LIP group showed that high-density lipiodol was deposited in the tumors in CT images. Histopathologic findings showed an almost complete central necrosis coagulation of tumors in the SPIO-DOX-LIP group, and the tumor necrosis percentage and tumor apoptosis index were significantly increased in the SPIO-DOX-LIP group compared to those in other 3 groups (P<0.05).â© Conclusion: This novel drug-delivery system of SPIO nano-drug carrier together with LIP is safe and feasible when it is used for transhepatic arterial embolization for liver tumor. It provides an excellent MR and CT visualization and improves the therapeutic efficacy for the treatment of rabbit VX2 liver tumor.
Assuntos
Antineoplásicos/administração & dosagem , Quimioembolização Terapêutica/métodos , Óleo Etiodado/administração & dosagem , Compostos Férricos/administração & dosagem , Artéria Hepática , Neoplasias Hepáticas/terapia , Nanopartículas de Magnetita/administração & dosagem , Alanina Transaminase/sangue , Animais , Antineoplásicos/sangue , Aspartato Aminotransferases/sangue , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Estudos de Viabilidade , Compostos Férricos/sangue , Marcação In Situ das Extremidades Cortadas , Neoplasias Hepáticas/sangue , Coelhos , Distribuição AleatóriaRESUMO
Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.
Assuntos
Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/farmacocinética , Substâncias Protetoras/farmacocinética , Administração Oral , Animais , Antineoplásicos/sangue , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Cloridrato de Erlotinib/sangue , Masculino , Extratos Vegetais/química , Plantas Medicinais/química , Substâncias Protetoras/metabolismo , Quinazolinas/sangue , Ratos , Ratos Sprague-Dawley , GencitabinaRESUMO
CONTEXT: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb-drug interaction remains unknown. OBJECTIVE: This study investigates the herb-drug interaction between triptolide and sorafenib. MATERIALS AND METHODS: The effects of triptolide (10 mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100 mg/kg) in rats, and blood samples were collected within 48 h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems. RESULTS: The results showed that the Cmax (low dose: 72.38 ± 8.76 versus 49.15 ± 5.46 ng/mL; medium dose: 178.65 ± 21.05 versus 109.31 ± 14.17 ng/mL; high dose: 332.81 ± 29.38 versus 230.86 ± 9.68 ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t1/2 of sorafenib increased significant (p < 0.05) from 9.02 ± 1.16 to 12.17 ± 2.95 h at low dose with the pretreatment of triptolide. Triptolide has little effect on the absorption of sorafenib in Caco-2 cell transwell model. However, triptolide could significantly decrease the intrinsic clearance rate of sorafenib from 51.7 ± 6.37 to 32.4 ± 4.43 µL/min/mg protein in rat liver microsomes. DISCUSSION AND CONCLUSIONS: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos/farmacocinética , Diterpenos/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Niacinamida/análogos & derivados , Fenantrenos/farmacologia , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Biotransformação/efeitos dos fármacos , Células CACO-2 , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Compostos de Epóxi/farmacologia , Feminino , Meia-Vida , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Niacinamida/administração & dosagem , Niacinamida/sangue , Niacinamida/metabolismo , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/sangue , Compostos de Fenilureia/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Ratos Sprague-Dawley , SorafenibeRESUMO
Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans.