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1.
Int J Nanomedicine ; 15: 5445-5458, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801699

RESUMO

5-Fluorouracil (5-FU) has become one of the most widely employed antimetabolite chemotherapeutic agents in recent decades. It is considered a first line antineoplastic agent for the treatment of colorectal cancer. Unfortunately, chemotherapy with 5-FU has several limitations, including its short half-life, high cytotoxicity and low bioavailability. In order to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency, many scientific groups have focused on designing a new delivery system to successfully deliver 5-FU to tumor sites. We provide a comprehensive review on different strategies to design effective delivery systems, including nanoformulations, drug-conjugate formulations and other strategies for the delivery of 5-FU to colorectal cancer. Furthermore, co-delivery of 5-FU with other therapeutics is discussed. This review critically highlights the recent innovations in and literature on various types of carrier system for 5-FU.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Fluoruracila/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Disponibilidade Biológica , Portadores de Fármacos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacocinética , Humanos , Nanoestruturas/administração & dosagem , Nanoestruturas/química
2.
Surgery ; 168(3): 448-456, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32620306

RESUMO

BACKGROUND: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. RESULTS: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). CONCLUSION: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Infusões Intralesionais/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral/transplante , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Modelos Animais de Doenças , Humanos , Infusões Intravenosas/métodos , Masculino , Camundongos , Pâncreas/irrigação sanguínea , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Pressão , Distribuição Tecidual
3.
PLoS One ; 15(4): e0231745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298392

RESUMO

PURPOSE: To develop a technique to compare the intra-tumoral distribution of the drug gemcitabine, its surrogate [18F]-fluoroarabinocytosine ([18F]-FAC) and related chemotherapeutics 5-FU and capecitabine in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Using a KPC-organoid derived model of PDAC, we obtained autoradiographic images of the tumor distribution of, [14C]-gemcitabine, [14C]-5-FU, [3H]-capecitabine. These were compared indirectly by co-administering [18F]-FAC, a close analog of gemcitabine with a proven equivalent intra-tumor distribution. The short half-life of 18F allows for clean separation of 3H/14C labeled drugs in specimens by dual isotope digital autoradiography. Autoradiographic images of [14C]-gemcitabine, [3H]-capecitabine and [14C]-5-FU were each correlated to [18F]-FAC on a pixel-by-pixel basis. The tumor drug penetration was compared using cumulative histograms. RESULTS: Gemcitabine distribution correlated strongly with FAC as expected. 5-FU also gave a similar microdistribution to that of FAC, whereas no correlation was found between capecitabine or its metabolic products and FAC distribution. Accumulation of Gemcitabine and 5-FU was lower in hypoxic regions of the tumor, whereas no such correlation was observed for capecitabine and its metabolites. CONCLUSIONS: Gemcitabine and 5-FU target the same regions of the tumor, leaving hypoxic cells untreated. Capecitabine metabolites penetrate further into the tumor but it is yet to be determined whether these metabolites are the active form of the drug.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Carcinoma Ductal Pancreático/metabolismo , Desoxicitidina/análogos & derivados , Fluoruracila/farmacocinética , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Hipóxia Celular , Desoxicitidina/farmacocinética , Técnicas de Diagnóstico por Radioisótopos , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Organoides/patologia , Organoides/transplante , Neoplasias Pancreáticas/diagnóstico por imagem
4.
Cancer Chemother Pharmacol ; 85(5): 941-947, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32279102

RESUMO

PURPOSE: The aim of this study was to investigate the association between changes in the levels of vascular endothelial growth factors (VEGFs) after treatment with bevacizumab and gemcitabine (Bev-Gem) and the clinical outcome. METHODS: Platinum-resistant ovarian cancer patients treated with Bev-Gem therapy at our hospital between 2014 and 2018 were identified. Serum VEGF levels at the first and second treatment cycle were measured by ELISA. All patients were categorized into two groups-patients with > 50% decrease in serum VEGF-A levels (Group A) and patients with < 50% decrease serum VEGF-A levels (Group B). The association between clinical outcome and serum VEGF levels was investigated between the two groups. RESULTS: Among 18 patients, 10 were in Group A and 8 in Group B. Group A exhibited a lower response rate (0% vs.75% p < 0.01) and clinical benefit rate (60% vs.100% p = 0.02) than Group B. The median serum VEGF-A level of Group A before the first cycle of Bev-Gem therapy was higher than that in Group B (61.2 vs. 3.7 pg/mL, p < 0.01). Group A exhibited worse PFS (7 vs., 10 months, p < 0.01) and OS (17 vs. 26 months, p = 0.04) than Group B. There were more patients with > 10% increase in serum VEGF-B levels in Group A than in Group B (p < 0.01). CONCLUSION: The rapid decrease in VEGF-A levels and the resultant increase in serum VEGF-B levels might be associated with an unfavorable clinical outcome. Large-scale studies are needed to further examine these results.


Assuntos
Bevacizumab , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Fator A de Crescimento do Endotélio Vascular/sangue , Fator B de Crescimento do Endotélio Vascular/sangue , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/farmacocinética , Biomarcadores Farmacológicos/sangue , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Progressão da Doença , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Valor Preditivo dos Testes , Prognóstico
5.
Cancer Chemother Pharmacol ; 85(5): 881-897, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32246190

RESUMO

PURPOSE: High-dose methotrexate (HD-MTX) is widely used in the treatment of non-Hodgkin lymphoma (NHL), but the pharmacokinetic properties of HD-MTX in Chinese adult patients with NHL have not yet been established through an approach that integrates genetic covariates. The purposes of this study were to identify both physiological and pharmacogenomic covariates that can explain the inter- and intraindividual pharmacokinetic variability of MTX in Chinese adult patients with NHL and to explore a new sampling strategy for predicting delayed MTX elimination. METHODS: A total of 852 MTX concentrations from 91 adult patients with NHL were analyzed using the nonlinear mixed-effects modeling method. FPGS, GGH, SLCO1B1, ABCB1 and MTHFR were genotyped using the Sequenom MassARRAY technology platform and were screened as covariates. The ability of different sampling strategies to predict the MTX concentration at 72 h was assessed through maximum a posteriori Bayesian forecasting using a validation dataset (18 patients). RESULTS: A two-compartment model adequately described the data, and the estimated mean MTX clearance (CL) was 6.03 L/h (9%). Creatinine clearance (CrCL) was identified as a covariate for CL, whereas the intercompartmental clearance (Q) was significantly affected by the body surface area (BSA). However, none of the genotypes exerted a significant effect on the pharmacokinetic properties of MTX. The percentage of patients with concentrations below 0.2 µmol/L at 72 h decreased from 65.6 to 42.6% when the CrCL decreased from 90 to 60 ml/min/1.73 m2 with a scheduled dosing of 3 g/m2, and the same trend was observed with dose regimens of 1 g/m2 and 2 g/m2. Bayesian forecasting using the MTX concentrations at 24 and 42 h provided the best predictive performance for estimating the MTX concentration at 72 h after dosing. CONCLUSIONS: The MTX population pharmacokinetic model developed in this study might provide useful information for establishing personalized therapy involving MTX for the treatment of adult patients with NHL.


Assuntos
Técnicas de Genotipagem/métodos , Linfoma não Hodgkin , Taxa de Depuração Metabólica/genética , Metotrexato/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Antimetabólitos Antineoplásicos/farmacocinética , Teorema de Bayes , Superfície Corporal , China/epidemiologia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/metabolismo , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos
6.
Cancer Chemother Pharmacol ; 85(5): 869-880, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32240335

RESUMO

PURPOSE: Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication. METHODS: Rats orally received 180 mg/kg of capecitabine once a day for two weeks. Blood samples were collected nine times, and plasma concentration was measured on day 1, 7, and 14. The liver and small intestine were removed after blood sampling and were used in vitro to evaluate metabolic enzyme activities of carboxylesterase, cytidine deaminase, and thymidine phosphorylase. A physiologically based pharmacokinetic (PBPK) model was developed using in vitro results. RESULTS: Area under the plasma concentration-time curve from 0 h to infinity of 5-FU on day 7 and day 14 was significantly lower than that on day 1. Intrinsic clearance of thymidine phosphorylase in the liver on day 7 and day 14 was 1.4 and 1.3 times lower than that on day 1, respectively. The PBPK model described the observed plasma concentration of capecitabine and its metabolites. CONCLUSION: The decreased plasma concentration of capecitabine was caused by decreased metabolic enzyme activity. Efficacy can be improved by dose adjustment of capecitabine based on metabolic enzyme activities, using the PBPK model.


Assuntos
Capecitabina/farmacocinética , Carboxilesterase/metabolismo , Neoplasias Colorretais , Citidina Desaminase/metabolismo , Fluoruracila/farmacocinética , Timidina Fosforilase/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Biomarcadores Farmacológicos/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Relação Dose-Resposta a Droga , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pró-Fármacos/farmacocinética , Ratos , Distribuição Tecidual
7.
Sci Rep ; 10(1): 2711, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066801

RESUMO

Capecitabine is selectively converted from 5'-DFUR to 5-fluorouracil (5-FU) in tumours by thymidine phosphorylase (TP). We investigated the addition of 5-nitrouracil (5-NU), a TP inhibitor, into blood samples for precise measurements of plasma 5-FU concentrations. The plasma concentration of 5-FU was measured after capecitabine administration. Two samples were obtained at 1 or 2 h after capecitabine administration and 5-NU was added to one of each pair. Samples were stored at room temperature or 4 °C and 5-FU concentrations were measured immediately or 1.5 or 3 h later. The mean plasma 5-FU concentration was significantly higher at room temperature than at 4 °C (p < 0.001). The 5-FU concentration was significantly increased in the absence of 5-NU than in the presence of 5-NU (p < 0.001). The 5-FU change in concentration was greater in the absence of 5-NU, and reached 190% of the maximum compared with baseline. A significant interaction was found between temperature and 5-NU conditions (p < 0.001). Differences between the presence or absence of 5-NU were greater at room temperature than under refrigerated conditions. 5-FU plasma concentrations after capecitabine administration varied with time, temperature, and the presence or absence of 5-NU. This indicates that plasma concentrations of 5-FU change dependent on storage conditions after blood collection.


Assuntos
Antimetabólitos Antineoplásicos/sangue , Capecitabina/sangue , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/sangue , Timidina Fosforilase/antagonistas & inibidores , Uracila/análogos & derivados , Adulto , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Biotransformação , Capecitabina/farmacocinética , Capecitabina/farmacologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Fígado/metabolismo , Masculino , Temperatura , Timidina Fosforilase/metabolismo , Fatores de Tempo , Uracila/farmacologia
8.
Biopharm Drug Dispos ; 41(3): 101-110, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32017134

RESUMO

Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic one-compartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CLi = 9.23× (1 + 0.0005× (θCrCL -105.78)) × (1 + 0.0017× (θWT -16)) × eηcl,i (L/h), IF (θDEX ) CLi = 1.19× CLi (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Metotrexato/farmacocinética , Modelos Biológicos , Adolescente , Antimetabólitos Antineoplásicos/sangue , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Masculino , Metotrexato/sangue
9.
Drug Metab Pharmacokinet ; 35(1): 124-130, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31964620

RESUMO

Decitabine (DAC), a DNA methylation inhibitor, is transported into cancer cells mainly via equilibrative nucleoside transporter 1 (ENT1) and subsequently phosphorylated by deoxycytidine kinase (dCK). We previously reported that apparent DAC uptake into cells may be described using a simple compartment model with clearance for facilitated diffusion (PS) and subsequent phosphorylation (CLmet). In the present study, time course of apparent intracellular [3H]-DAC uptake was analyzed numerically, and PS and CLmet values were calculated using the compartment model in human colon cancer HCT116 cells. PS at 0.1 µM [3H]-DAC was markedly decreased in the presence of 100 µM irinotecan or etoposide, while CLmet was markedly decreased in the presence of 100 µM cytarabine or gemcitabine. CLmet at 0.1-10 µM [3H]-DAC varied in a concentration-dependent manner and was described by Michaelis-Menten parameters Km,met and Vmax,met. In conclusion, DAC uptake mainly via ENT1 may be described by a bidirectional first-order kinetic parameter, while phosphorylation by dCK may be described by Michaelis-Menten parameters.


Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Decitabina/metabolismo , Decitabina/farmacocinética , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Dinâmica não Linear , Células HCT116 , Humanos , Cinética , Fosforilação , Trítio/química
10.
Pediatr Blood Cancer ; 67(4): e28123, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31867853

RESUMO

High-dose methotrexate (HD-MTX; 12 g/m2 ) is part of standard therapy for pediatric osteosarcoma (OS). Risk factors associated with MTX toxicity in children with OS are not well defined. We investigated the association between peak MTX levels (four-hour) and delayed MTX clearance or treatment toxicity. Information was retrieved from electronic medical records of 33 OS patients treated with HD-MTX at Texas Children's Hospital from 2008 to 2015. We found that the four-hour MTX level did not contribute to toxicity or delayed MTX clearance. We demonstrated that certain demographic characteristics are associated with delayed clearance and increased toxicity.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Metotrexato/efeitos adversos , Osteossarcoma/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Metotrexato/sangue , Metotrexato/farmacocinética , Estudos Retrospectivos , Fatores de Risco
11.
Mater Sci Eng C Mater Biol Appl ; 107: 110330, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761209

RESUMO

The present study focused on the development of electric stimuli drug release carrier based on transition metal dicgalcogenides. First, tungsten disulfide (WS2) was exfoliated and functionalized using thiol chemistry with various thiol-terminated ligands such as thioglycolic acid (TGA), mercaptosuccinic acid (MSA), and 2-ethanethiol (2ET). The exfoliated WS2 underwent non-covalent coating with an electrically conductive polypyrrole (PPy) for functionalization, of which MSA-WS2-PPy achieved the highest 5-FU (anticancer drug) loading. An electrically-stimulated drug release experiment showed that TGA-WS2-PPy achieved a higher drug release (90%) than MSA-WS2-PPy (70%) and 2ET-WS2-Ppy (35%). The TGA-WS2-PPy exhibited swelling/recombination between PPY and MSA-WS2 substrate under electrical stimulation, resulting in the highest 5-FU release. From the MTT assay result, there was no significant toxicity observed for TGA-WS2-PPy-FU on HaCaT cells, indicating the biocompatibility of TGA-WS2-PPy-FU in the absence of electrical stimulation. However, HaCaT cells died when incubated with TGA-WS2-PPy-FU under electrical stimulation. Finally, Raman mapping studies for TGA-WS2-PPy drug release in the skin of nude mice demonstrated that the carrier penetrated deeper into the skin of the mice while other systems failed to exhibit significant effects under electrical stimulation. The present study offers a novel approach in developing a non-invasive electrically-stimulated drug release system based on WS2 and an externally-controlled delivery model.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanocompostos/química , Polímeros/química , Pirróis/química , Pele/efeitos dos fármacos , Compostos de Tungstênio/química , Administração Cutânea , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Linhagem Celular , Dissulfetos/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Estimulação Elétrica , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos ICR , Camundongos Nus , Nanocompostos/administração & dosagem , Análise Espectral Raman
12.
Cancer Chemother Pharmacol ; 85(1): 21-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31673826

RESUMO

PURPOSE: To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient. METHODS: A prospective study was developed in 50 children (1-15 years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48 h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX. RESULTS: A two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model. CONCLUSIONS: The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Superfície Corporal , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , Seguimentos , Humanos , Lactente , Masculino , México/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Estudos Prospectivos , Distribuição Tecidual
13.
Int J Pharm ; 573: 118718, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31756441

RESUMO

Intestinal mono-carboxylate transporter 1 (MCT1) plays an important role in the oral absorption of short-chain fatty acids that were used as oxidative metabolite. However, the prodrug strategy targeting intestinal MCT1 for oral delivery is rarely exploited. The oral bioavailability of Gemcitabine (Gem) is low mainly due to its poor intestinal permeability and rapid metabolism. Herein, a facile di-acid mono-amidation strategy was firstly developed to target MCT1 for oral chemotherapy. The N4-amino group of Gem is mono-amidated with di-acids containing different carbon chain lengths, which could recognize intestinal MCT1 and are bio-activated at physiological pH independent of the hydrolysis enzymes. The adipic acid-Gem shows higher MCT1 affinity, better gastrointestinal tract stability (3-fold), improved oral bioavailability (8.8-fold), and less gastrointestinal toxicity in comparison to Gem. Moreover the bio-activation rate of the prodrugs decreases with the increased fatty acid chain length of the linkage under physiological conditions. In summary, we present the first evidence that MCT1 could act as a new target for oral prodrug delivery, and that the linkage could modify the bio-activation rate for achieving optimal oral bioavailability. Our findings provide novel knowledge to rationally design intestinal transporter-targeting oral carrier prodrug.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Absorção Intestinal , Transportadores de Ácidos Monocarboxílicos/metabolismo , Simportadores/metabolismo , Administração Oral , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Ciclização , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Pró-Fármacos , Ratos , Ratos Wistar
14.
Medicina (Kaunas) ; 55(12)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795149

RESUMO

BACKGROUND AND OBJECTIVES: Sialylation plays important roles in tumor progression. Our present study aimed to demonstrate the alteration of sialylation and its role in cholangiocarcinoma (CCA). MATERIALS AND METHODS: The α2,3- and α2,6-sialylation in CCA tissue was analyzed by lectin-histochemistry using Maackia amurensis lectin-II (MAL-II) and Sambucus nigra agglutinin (SNA). CCA cell lines were treated with the pan-sialylation inhibitor 3Fax-peracetyl-Neu5Ac (3F-Sia) followed by proliferation and chemosensitivity assays. RESULTS: MAL-II binding α2,3-Sialylated Glycan (MAL-SG) and SNA binding α2,6-Sialylated Glycan (SNA-SG) were both elevated in CCA compared with hyperplastic/dysplastic (HP/DP) and normal bile ducts (NBD). The positive staining for MAL-SG or SNA-SG were found in 82% (61/74) of the CCA cases. Higher expression of MAL-SG in CCA was associated with shorter survival of the patients. The median survival of patients with high and low MAL-SG were 167 and 308 days, respectively, with overall survival of 233 days, suggesting the involvement of MAL-SG in CCA progression. MAL-SG expression of CCA cell lines was markedly decreased after treatment with 3F-Sia for 48 to 72 h. While proliferation of CCA cells were not affected by 3F-Sia treatment, their susceptibility to 5-fluorouracil (5-FU) was significantly enhanced. These results suggest that sialylation is involved in the development of 5-FU resistance and the sialylation inhibitor 3F-Sia can be used as a chemosensitizer for CCA. CONCLUSIONS: Sialylation is critically involved in the development of chemoresistance of CCA, and sialylation inhibitors may be used as a chemosensitizer in CCA treatment.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Fluoruracila/farmacocinética , Polissacarídeos/metabolismo , Sialoglicoproteínas/metabolismo , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Maackia , Lectinas de Plantas , Sialiltransferases/metabolismo
15.
Pharmacol Res Perspect ; 7(6): e00534, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31832201

RESUMO

Cytarabine (Ara-C) is a nucleoside analog used in the treatment of acute myeloid leukemia (AML). Despite the many years of clinical use, the identity of the transporter(s) involved in the disposition of Ara-C remains poorly studied. Previous work demonstrated that concurrent administration of Ara-C with nitrobenzylmercaptopurine ribonucleoside (NBMPR) causes an increase in Ara-C plasma levels, suggesting involvement of one or more nucleoside transporters. Here, we confirmed the presence of an NMBPR-mediated interaction with Ara-C resulting in a 2.5-fold increased exposure. The interaction was unrelated to altered blood cell distribution, and subsequent studies indicated that the disposition of Ara-C was unaffected in mice with a deficiency of postulated candidate transporters, including ENT1, OCTN1, OATP1B2, and MATE1. These studies indicate the involvement of an unknown NBMPR-sensitive Ara-C transporter that impacts the pharmacokinetic properties of this clinically important agent.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Citarabina/farmacocinética , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Interações Medicamentosas , Transportador Equilibrativo 1 de Nucleosídeo/antagonistas & inibidores , Transportador Equilibrativo 1 de Nucleosídeo/genética , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Camundongos , Camundongos Knockout , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Simportadores/genética , Simportadores/metabolismo , Tioinosina/análogos & derivados , Tioinosina/farmacologia
16.
CPT Pharmacometrics Syst Pharmacol ; 8(12): 940-950, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31652031

RESUMO

Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-ß-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Di-Hidrouracila Desidrogenase (NADP)/genética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Capecitabina/química , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Feminino , Floxuridina/farmacocinética , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/genética , Variantes Farmacogenômicos , Pró-Fármacos
17.
Cancer Chemother Pharmacol ; 84(6): 1359-1363, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31641844

RESUMO

PURPOSE: The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Its prevalence may vary among African subpopulations and in African Americans. There is no information in other populations. Brazil has the biggest African population outside Africa. We studied for the first time the frequency of this mutation in African Brazilians. METHODS: We amplified exon 6 of DPYD extracted from genomic DNA of 79 healthy volunteers of genetically defined African ancestry from Southeast Brazil and 36 self-reported African descendants from Northeast Brazil in order to determine the prevalence of the variant Y186C in Brazilians of African ancestry. RESULTS: The variant Y186C was found in heterozygosity in two samples from Southeast (2.53%) and one from Northeast (2.77%) Brazil. Overall, the prevalence of this mutation in the 115 African Brazilians was 2.6%. CONCLUSIONS: The variant Y186C is prevalent among Brazilians of African ancestry and should be taken in account in targeted genotyping for fluoropyrimidine risk variants.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Deficiência da Di-Hidropirimidina Desidrogenase/etnologia , Di-Hidrouracila Desidrogenase (NADP)/genética , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Brasil/epidemiologia , Capecitabina/farmacocinética , Capecitabina/uso terapêutico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Voluntários Saudáveis , Humanos , Masculino , Mutação , Neoplasias/tratamento farmacológico , Prevalência
18.
Drug Des Devel Ther ; 13: 3281-3290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571830

RESUMO

Background: Ovarian cancer is the third leading cause of death among gynecological cancers in women in China. Chemotherapy is an important method for comprehensive treatment of ovarian cancer, but the curative effect is poor. Purpose: In this study, gemcitabine (GEM) -loaded RGD modified liposomes (LPs) were developed by the emulsification-solvent evaporation method and evaluated for their antitumor activity in vitro and in vivo. Methods: The physicochemical properties of LPs such as particle size, zeta potential and in vitro drug release were investigated. We also demonstrated the effect of RGD-GEM-PEG LPs in ovarian cancer. Results: RGD-PEG3500-DSPE GEM LPs had a uniform spherical morphology. The mean particle size and polydispersity index were determined to be 106.7 nm and 0.13 respectively. The ER% and DL% of the formulation were 79.6±3.1% and 6.1±1.4% respectively. Compared with the free drug, RGD modified GEM LPs had sustained-release properties in vitro. In vivo, compared with the DiD-RGD-PEG3500-DSPE GEM LPs group, free DiD-GEM and DiD-GEM LPs had no obvious fluorescence intensity in tumor of mice at all times, indicating that ordinary liposomes and drugs had no tumor targeting function. RGD-PEG3500-DSPE GEM LPs showed a superior antiproliferative effect on SKOV3 cells and had a better antitumor effect in vivo than non-modified LPs. Conclusion: These results indicated that RGD-PEG3500-DSPE GEM LPs were a promising candidate for antitumor drug delivery.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/metabolismo , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , China , Desoxicitidina/administração & dosagem , Desoxicitidina/metabolismo , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Lipossomos/química , Lipossomos/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Oligopeptídeos , Tamanho da Partícula , Ratos
19.
Cancer Chemother Pharmacol ; 84(6): 1339-1348, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31586225

RESUMO

PURPOSE: High-dose methotrexate (HD-MTX) is widely used in pediatric and adult oncology treatment regimens. This study aimed to develop a population pharmacokinetic model to characterize pediatric and adult MTX exposure across various disease types and dosing regimens, and to evaluate exposure-toxicity relationships. METHODS: MTX pharmacokinetic data from pediatric and adult patients were collected. A population pharmacokinetic model was developed to determine the effects of age, liver function, renal function, and demographics on MTX disposition. The final model was used in Monte Carlo simulations to generate expected exposures for different dosing regimens. The association of toxicity, determined through chart review, and MTX area under the curve (AUC) was modeled using logistic regression. RESULTS: The analysis included 5116 MTX concentrations from 320 patients (135 adult, age 19-79 years; 185 pediatric, age 0.6-19 years). Estimated glomerular filtration rate (eGFR) and treatment cycle number were independent predictors of clearance (CL). CL varied 2.1-fold over the range of study eGFR values and increased 14% for treatment cycle numbers greater than 7. Higher MTX AUC was associated with higher risk of nephrotoxicity in adults, and neurotoxicity and hepatotoxicity in pediatrics. CONCLUSIONS: This study represents one of the most comprehensive evaluations of HD-MTX PK across a wide range of ages and disease types. After accounting for differences in renal function, age did not impact CL, although toxicity patterns differed by age. The model allows for early identification of patients with slowed MTX clearance and at higher risk of toxicity.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Metotrexato/farmacocinética , Modelos Biológicos , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/toxicidade , Área Sob a Curva , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Feminino , Taxa de Filtração Glomerular , Humanos , Lactente , Masculino , Taxa de Depuração Metabólica , Metotrexato/administração & dosagem , Metotrexato/toxicidade , Pessoa de Meia-Idade , Neoplasias/sangue , Adulto Jovem
20.
Drug Des Devel Ther ; 13: 3127-3136, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564829

RESUMO

Purpose: S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients. Methods: This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method. Results: In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study. Conclusion: The new S-1 formulation met the Korean regulatory requirement for bioequivalence. Both S-1 formulations were well tolerated in all subjects.Clinical trial registry: https://cris.nih.go.kr CRIS KCT0003855.


Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Fluoruracila/farmacocinética , Ácido Oxônico/farmacocinética , Piridinas/farmacocinética , Neoplasias Gástricas/metabolismo , Tegafur/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Cromatografia Líquida , Estudos Cross-Over , Composição de Medicamentos , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/sangue , Piridinas/administração & dosagem , Piridinas/sangue , República da Coreia , Neoplasias Gástricas/química , Espectrometria de Massas em Tandem , Tegafur/administração & dosagem , Tegafur/sangue , Equivalência Terapêutica
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