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1.
J Pharm Biomed Anal ; 174: 728-733, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299453

RESUMO

Xiao-Ai-Ping injection (XAP) has been shown to be clinically effective in treatment of gastric carcinoma, liver cancer and lung cancer, when it was combined with anticancer drug paclitaxel (PTX). To analyze the effect of XAP on the pharmacokinetics of PTX, a liquid chromatography-tandem mass spectroscopy (LCMS/MS) assay method was developed and validated to quantify PTX simultaneously and its main metabolite 3'-p-hydroxypaclitaxel (C3'-OHP) in rat plasma. PTX and C3'-OHP were quantified using positive MRM mode. The analysis method was validated for specificity, recovery, carry-over, accuracy, precision, sample stability and dilution integrity under various storage conditions. The pharmacokinetic parameters were determined in rats after tail intravenous administration of 6 mg/mL PTX in the absence (control group) or presence of intraperitoneal administration of 10 mL/kg、20 mL/kg XAP (study groups). Compared to control group, the area under the plasma concentration-time curve (AUC) of PTX and C3'-OHP in study groups increased significantly following consecutive administration with XAP for 10 days. In conclusion, pretreatment with XAP enhanced the exposure of PTX and C3'-OHP. There would be herb-drug interaction happening between XAP and PTX in rats.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Interações Ervas-Drogas , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/farmacocinética , Calibragem , Cromatografia Líquida , Feminino , Modelos Lineares , Paclitaxel/sangue , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
2.
Artigo em Inglês | MEDLINE | ID: mdl-31276955

RESUMO

In spite of having a remarkable anti tumor activity against a wide variety of cancers, the clinical effectiveness of the major chemotherapeutic drug paclitaxel is often limited by the issues of drug resistance that hampers the therapeutic effectiveness of the drug. The combination of proton pump inhibitor with paclitaxel is an effective approach to overcome therapeutic resistance caused by the acidic microenvironment (Warburg effect) in tumor. In the present study a new simple, precise and selective liquid chromatography tandem mass spectrometry method was developed for quantification of paclitaxel and lansoprazole using esomeprazole as an internal standard and applied for the pharmacokinetic study of investigational paclitaxel - lansoprazole loaded PLGA nanoparticles. The developed method quantifies both the drugs simultaneously irrespective of their dissimilar stability concerns. The detection was exercised with multiple reaction-monitoring mode in positive ionization that yielded highly intense response of parent-product (m/z) transition pair 854.4 → 286.1, 370.1 → 251.9 and 346 → 198 for paclitaxel, lansoprazole and Esomeprazole respectively. The chromatographic separation was achieved using phenomenex Kinetex 5 µ C18 100A 50 × 3.0 mm column and a gradient mobile phase combination of ammonium acetate in deionized water (pH 6.8, 2 mM, w/v) and acetonitrile spiked with formic acid (1:1000, v/v ). This method showed good linearity over a concentration range of 10-320 ng/mL and 100-3200 ng/mL with correlation coefficient (R2) 0.98 and 0.94 for paclitaxel and lansoprazole respectively. Using liquid liquid extraction process both the drugs were extracted from rat plasma. The intra- and inter-day precision and accuracy values were within the variability limits and both the analytes were found to be stable throughout the freeze-thaw, auto-sampler, bench top and long term stability studies. The liquid chromatography tandem mass spectrometry method was successfully validated in accordance with United States Food and Drug administration guidelines and the results were within the acceptable limits. The liquid chromatography tandem mass spectrometry method was successfully utilized for the pharmacokinetic investigation of experimental paclitaxel - lansoprazole loaded PLGA nanoparticles in rat plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Lansoprazol/sangue , Paclitaxel/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Feminino , Lansoprazol/química , Lansoprazol/farmacocinética , Masculino , Paclitaxel/química , Paclitaxel/farmacocinética , Ratos
3.
Int J Nanomedicine ; 13: 3625-3640, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983558

RESUMO

BACKGROUND: Lumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects. METHODS AND RESULTS: Here, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(ε-benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied. CONCLUSION: We propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits.


Assuntos
Albuminas/uso terapêutico , Endopeptidases/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Albuminas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina B1/metabolismo , Portadores de Fármacos/química , Endopeptidases/sangue , Endopeptidases/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lisina/análogos & derivados , Lisina/síntese química , Lisina/química , Masculino , Microvasos/patologia , Peso Molecular , Paclitaxel/sangue , Paclitaxel/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polilisina/análogos & derivados , Polilisina/síntese química , Polilisina/química , Ratos Sprague-Dawley , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologia
4.
Chin J Integr Med ; 23(1): 70-75, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27679442

RESUMO

OBJECTIVE: To investigate the effect of Shaoyao Gancao Decoction (, SGD) on the pharmacokinetics of intravenously administered paclitaxel in rats. METHODS: Paclitaxel was intravenously administered to rats (3 mg/kg) with or without the concomitant administration of SGD (752 mg/kg, a single day or 14 consecutive days pretreatment). The paclitaxel in the serum was quantified using a simple and rapid ultra performance liquid chromatography (UPLC) method for the pharmacokinetic study. The pharmacokinetic parameters were calculated via a non-compartment model using the computer program DAS 2.0. RESULTS: The pharmacokinetic parameters of paclitaxel were significantly altered in response to 14 consecutive days of pretreatment with SGD. The area under the curve (AUC0-t, from 4 820±197 to 4 205±186 ng·mL-1·-1) and AUC0-∞ (from 5 237±280 to 4 514±210 ng·mL-1·-1) significantly decreased in response to the 14-day pretreatment with SGD. The values of Vdss (L/kg) were 10.74±1.08 and 9.35±0.49, those of CL (L/kg) were 0.67±0.03 and 0.57±0.03 and the t1/2 (h) values were 11.17±0.84 and 11.32±0.93, respectively, for the 14-day SGD pretreatment and intravenous paclitaxel alone. The AUC0-t and AUC0-∞ values decreased by 13% and 14% (P<0.01), respectively. The area under the curve decreased signifificantly (P<0.01), and the total clearance increased by 1.2-fold (P<0.01), after 14 consecutive days of pretreatment with SGD. A single-day pretreatment with SGD did not signifificantly affect the pharmacokinetic parameters of paclitaxel. CONCLUSIONS: SGD administration for 14 consecutive days increased the metabolism of paclitaxel, while a 1-day pretreatment had little effect. The results would contribute important information to the study on interaction between Chinese medicines and chemotherapy and also help to utilize SGD better in the adjunctive therapy of cancer patients.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Injeções Intravenosas , Masculino , Paclitaxel/sangue , Paclitaxel/química , Ratos Sprague-Dawley , Padrões de Referência , Fatores de Tempo
5.
Acta Pharmacol Sin ; 38(2): 264-276, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27867186

RESUMO

Shenmai injection (SMI) is a Chinese patent-protected injection, which was mainly made of Red Ginseng and Radix Ophiopogonis and widely used for treating coronary heart disease and tumors by boosting Qi and nourishing Yin. In this study we examined whether SMI could produce direct synergetic effects on the cytoxicity of adriamycin (ADR) and paclitaxel (PTX) in colorectal cancers in vivo and in vitro, and explored the underlying pharmacokinetic mechanisms. BALB/c nude mice with LoVo colon cancer xenografts were intraperitoneally injected with ADR (2 mg·kg-1·3d-1) or PTX (7.5 mg·kg-1·3d-1) with or without SMI (0.01 mL·g-1·d-1) for 13 d. Co-administration of SMI significantly enhanced the chemotherapeutic efficacy of ADR and PTX, whereas administration of SMI alone at the given dosage did not produce visible anti-cancer effects, The chemosensitizing action of SMI was associated with increased concentrations of ADR and PTX in the plasma and tumors. In Caco-2 and LoVo cells in vitro, co-treatment with SMI (2 µL/mL) significantly enhanced the cytotoxicity of ADR and PTX, and resulted in some favorable pharmacokinetic changes in the subcellular distribution of ADR and PTX. In addition, SMI-induced intracellular accumulation of ADR was closely correlated with the increased expression levels of P-glycoprotein in 4 colon cancer cell lines (r2=+0.8558). SMI enhances the anti-cancer effects of ADR and PTX in colon cancers in vivo and in vitro by improving the subcellular distributions of ADR and PTX.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Doxorrubicina/farmacologia , Doxorrubicina/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Doxorrubicina/sangue , Combinação de Medicamentos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/análise , Humanos , Camundongos , Paclitaxel/sangue , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Sci Rep ; 6: 25659, 2016 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-27157103

RESUMO

Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Humanos , Concentração Inibidora 50 , Injeções Intraperitoneais , Injeções Intravenosas , Isomerismo , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Piperidinas/sangue , Quinolinas/sangue , Ratos Sprague-Dawley
7.
Phytomedicine ; 22(5): 573-8, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25981924

RESUMO

BACKGROUND: Taxus chinensis (Pilger) Rehd is widely distributed in China and the northern hemisphere, and the most popular medicinal component isolated from Taxus chinensis is paclitaxel (PTX), which has now become the first-line chemotherapeutic drug for breast cancer and ovarian cancer. Oral administration of pure PTX as a potential anti-cancer agent is compromised by low bioavailability. HYPOTHESIS/PURPOSE: In the clinical practice of traditional Chinese medicine, drug co-administration in the form of mixtures or formula could achieve pharmacokinetic/pharmacodynamic synergies. In this study, we aimed to investigate whether there exist any 'inherent' phytochemical synergy from Taxus chinensis extract that could improve PTX bioavailability. STUDY DESIGN: Pharmacokinetic study of PTX after oral administration of Taxus chinensis extracts or single PTX was performed. In addition, comparative cytotoxic studies were carried out on the MCF-7 breast cancer cell lines. METHODS: The plasma concentrations of PTX were determined using a validated high performance chromatography tandem mass spectrometry method. The cytotoxicity was compared using the MTT assay. RESULTS: Oral administration of taxane fractions isolated from Taxus chinensis (containing 17.2% PTX) could achieve remarkably higher blood concentration and systemic exposure of PTX in rats, while the retention of PTX was significantly improved. Further tissue distribution analysis revealed that the penetration of PTX into major tissues was drastically increased compared with that of single PTX. In addition, in MCF-7 cells, the co-existing components in taxane mixtures could strengthen the inhibitory effects of PTX on tumor cell proliferation. CONCLUSION: Together, these results support that administration of PTX in the form of taxane mixtures may become a novel approach to improve the poor bioavailability of PTX. Moreover, the inherent synergy from Taxus chinensis taxane extracts promises a novel strategy to strengthen PTX efficacy.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Paclitaxel/farmacocinética , Taxoides/farmacocinética , Taxus/química , Administração Oral , Animais , Antineoplásicos Fitogênicos/sangue , Disponibilidade Biológica , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Sinergismo Farmacológico , Humanos , Células MCF-7 , Masculino , Camundongos Endogâmicos ICR , Estrutura Molecular , Paclitaxel/sangue , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Ratos Sprague-Dawley , Taxoides/administração & dosagem
8.
J Pharm Biomed Anal ; 107: 346-54, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-25645339

RESUMO

A rapid, sensitive and reliable method has been developed and validated for the simultaneous determination of seven taxoids including 10-deacetylbaccatin III (10-DAB III), baccatin III, 5-epi-canadensene, taxinine M, 10-deacetyltaxol (10-DAT), cephalomannine and paclitaxel in rat plasma using docetaxel as the internal standard (IS). The plasma samples were pretreated by liquid-liquid extraction with methyl tert-butyl ether. The chromatographic separation was achieved on a C18 column (50 mm × 2.1 mm, 1.8 µm, Waters, USA) with a gradient elution program consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. Detection was performed under the selected reaction monitoring (SRM) scan using an electrospray ionization (ESI) in the positive ion mode. The mass transitions were as follows: m/z 567.4→444.9 for 10-DAB III, m/z 609.0→549.3 for baccatin III, m/z 617.4→496.9 for 5-epi-canadensene, m/z 709.6→649.3 for taxinine M, m/z 834.8→307.9 for 10-DAT, m/z 854.5→285.4 for cephalomannine, m/z 876.8→307.3 for paclitaxel and m/z 830.8→549.6 for IS, respectively. All calibration curves exhibited good linearity (r(2)>0.99) over a wide concentration range for all components. The intra-day and inter-day precisions at three different levels were both less than 14.3% in terms of relative standard deviation (RSD) and the accuracies ranged from -8.3% to 14.8% in terms of relative error (RE). The extraction recoveries of the seven compounds ranged from 62.5% to 100.5%. The developed method was successfully applied to the pharmacokinetic study of the seven taxoids in rat plasma after oral administration of the crude extract of the twigs and leaves of Taxus yunnanensis.


Assuntos
Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Plasma/química , Taxoides/sangue , Taxoides/química , Taxus/química , Administração Oral , Alcaloides/sangue , Alcaloides/química , Animais , Hidrocarbonetos Aromáticos com Pontes/sangue , Hidrocarbonetos Aromáticos com Pontes/química , Cromatografia Líquida de Alta Pressão/métodos , Docetaxel , Masculino , Éteres Metílicos/sangue , Éteres Metílicos/química , Paclitaxel/sangue , Paclitaxel/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos
9.
Pharm Res ; 31(10): 2876-86, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24848338

RESUMO

PURPOSE: A strong pharmacokinetic rational exists for the use of (Hyperthermic) Intraperitoneal Perioperative Chemotherapy in peritoneal carcinomatosis. However, controversy remains regarding the optimal treatment strategies. Paclitaxel is believed to be a good compound for IPEC treatment because of its favourable pharmacokinetic properties. METHODS: Rat experiments were set up to gain insight in PTX's pharmacokinetics and pharmacodynamics after IPEC treatment with Taxol®. Afterwards a Pharmacokinetic-Pharmacodynamic model was developed, that concurrently describes plasma and tumour exposure post IPEC dosing. Moreover, the developed model adequately describes the time-course of tumour apoptosis as well as the treatment effect on tumour volume. RESULTS: We show that the complex absorption processes underlying PTX absorption from the peritoneal cavity post IPEC dosing, give rise to a markedly non-linear dose response relationship. Furthermore, we show that, in order to optimize treatment efficiency whilst concurrently minimizing the possibility of systemic toxicities, lowering the dose and extending exposure to the cytotoxic solution is the way forward. CONCLUSIONS: Based on the close resemblance between tumour exposure in our animal model and tumour exposure in patients treated under similar conditions, we hypothesise that, according to our findings in the rat, in the treatment of PC using IPEC administration of PTX, less is truly more.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Quimioterapia do Câncer por Perfusão Regional/métodos , Modelos Biológicos , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Neoplasias Peritoneais/tratamento farmacológico , Absorção Fisiológica , Animais , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipertermia Induzida , Dinâmica não Linear , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Paclitaxel/sangue , Paclitaxel/uso terapêutico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Ratos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Pharm ; 437(1-2): 192-202, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22944301

RESUMO

Multifunctional nanoparticles (NPs) were prepared based on temperature-induced phase transition in a molten mixture of Lipiodol(®), Tween 80, paclitaxel (PTX), and Pluronic F-68, wherein the Lipiodol(®)/Tween 80 mixture is used as a solubilizer for PTX, and Pluronic F-68 is used for the stabilization of the molten mixture. The morphology and size distribution of optimized multifunctional NPs were observed using transmittance electron microscopy (TEM) and a particle size analyzer. In the optical imaging of tumor-bearing mice using a near-infrared fluorescence (NIRF) imaging system, the multifunctional NPs were evaluated in terms of a time-dependent excretion profile, in vivo biodistribution and tumor-targeting capability compared to free fluorescence dye. In addition, the prolonged circulation of multifunctional NPs was confirmed by enhancement of the blood-pool in live animals using a micro-CT imaging system, because iodine-containing Lipiodol(®) has an X-ray enhancement property. Finally, the anti-tumor efficacy of multifunctional NPs was monitored by injecting the multifunctional NPs into the tail veins of tumor-bearing mice. The multifunctional NPs showed excellent tumor targetability and anti-tumor efficacy in tumor-bearing mice, caused by the enhanced permeation and retention (EPR) effect.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Óleo Etiodado/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Imagem Molecular , Nanopartículas/química , Neoplasias/patologia , Paclitaxel/sangue , Paclitaxel/química , Paclitaxel/farmacocinética , Transição de Fase , Poloxâmero/química , Polissorbatos/química , Temperatura , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Arch Pharm Res ; 35(3): 509-16, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22477198

RESUMO

Paclitaxel is a P-gp substrate and metabolized via CYP2C and 3A subfamily in rats. It has been reported that cysteine causes the changes in expression of CYP isozymes and intestinal P-gp mediated efflux activity in rats. Thus, the effects of cysteine on the pharmacokinetics of intravenous and oral paclitaxel were investigated in rats. After intravenous administration of paclitaxel (30 mg/kg) to control (CON), single cysteine treatment (ST) and cysteine treatment for a week (CT) rats, the pharmacokinetic parameters were comparable among three groups of rats. Also the pharmacokinetic parameters between CON and ST rats were comparable after oral administration of paclitaxel (30 mg/kg) to rats. These results are consistent with that oral cysteine supplement on a single day did not considerably inhibit the metabolism of paclitaxel via hepatic and/or intestinal CYP3A subfamily and P-gp mediated efflux of paclitaxel in the liver and/or intestine both after intravenous and oral administration to rats. After oral administration of paclitaxel (30 mg/kg) to rats, the greater AUC(06 h) in CT rats was mainly due to that oral cysteine supplement for seven consecutive days enhanced the gastrointestinal absorption of paclitaxel compared with those in CON and ST rats.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Cisteína/farmacologia , Paclitaxel/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Área Sob a Curva , Biotransformação , Cisteína/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Injeções Intravenosas , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Ligação Proteica , Ratos , Ratos Sprague-Dawley
12.
J Vasc Interv Radiol ; 21(8): 1262-70, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20656224

RESUMO

PURPOSE: Paclitaxel is an antiproliferative agent in drug-eluting stents with largely unknown tissue interaction. Toxicity might result from overdosage and/or accumulation. Part 1 of this two-step study investigated how paclitaxel uptake depends on dose density, coronary drug transfer kinetics, and elution efficacy. MATERIALS AND METHODS: With cobalt chromium stents and Polyzene-F nanoscale coating, low, intermediate, and high paclitaxel dose densities (25 microg, 50 microg, and 150 microg per stent) were investigated in porcine right coronary arteries (RCAs). Coronary and myocardial tissue concentration measurements and determination of on-stent paclitaxel and plasma concentrations were performed at 2, 8, 24, and 72 hours. RESULTS: For all stents, uptake was similar at all time intervals (paclitaxel RCA concentration range, 1,610-33,300 ng). Low- and intermediate-dose stents showed similar RCA concentrations, but those for high-dose stents were three times greater. Residual on-stent paclitaxel concentration was not time-dependent, at 33.3% on low-, 30.6% on intermediate-, and 17.4% on high-dose stents. Paclitaxel was measurable in only the plasma immediately after stent placement, with a linear dose relationship and a timely regression: measurements in high-dose stents were 0.0454-0.656 ng/mL at 1 minute and 0.0329-0.0879 ng/mL at 5 minutes. Untreated control samples of the left coronary artery showed a linear dose-dependent concentration (12.6 ng/g, 21.2 ng/g, and 85.2 ng/g). CONCLUSIONS: Overall coronary paclitaxel uptake is fairly independent from the baseline overall dose density and, hence, depends on immediate binding mechanisms of the arterial wall. This is supported by the fact that, regardless of the applied dose density, the kinetics of paclitaxel uptake did not follow an exposure time pattern.


Assuntos
Angioplastia Coronária com Balão/instrumentação , Fármacos Cardiovasculares/farmacocinética , Materiais Revestidos Biocompatíveis , Vasos Coronários/metabolismo , Stents Farmacológicos , Inflamação/metabolismo , Paclitaxel/farmacocinética , Angioplastia Coronária com Balão/efeitos adversos , Animais , Disponibilidade Biológica , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/toxicidade , Ligas de Cromo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Relação Dose-Resposta a Droga , Feminino , Inflamação/induzido quimicamente , Inflamação/patologia , Modelos Animais , Miocárdio/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Paclitaxel/toxicidade , Polímeros , Desenho de Prótese , Suínos , Porco Miniatura , Distribuição Tecidual
13.
Pharmacology ; 85(6): 350-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20523105

RESUMO

Silibinin, a flavonoid, is an inhibitor of P-glycoprotein (P-gp)-mediated efflux transporters, and its oxidative metabolism is catalyzed by CYP3A4. The purpose of this study was to investigate the effect of oral silibinin on the bioavailability and pharmacokinetics of orally and intravenously administered paclitaxel in rats. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (4 mg/kg) administration in the presence and absence of silibinin (0.5, 2.5 or 10 mg/kg). The effect of silibinin on the P-gp as well as CYP3A4 activity was also evaluated. Silibinin inhibited CYP3A4 enzyme activity with an IC(50) of 1.8 mumol/l. In addition, silibinin significantly inhibited P-gp activity. Compared to the control group, silibinin significantly (p < 0.05 by 2.5 mg/kg, p < 0.01 by 10 mg/kg) increased the area under the plasma concentration-time curve (65.8-101.7% higher) of oral paclitaxel. Silibinin also significantly increased (p < 0.05 by 2.5 mg/kg, 31.0% higher; p < 0.01 by 10 mg/kg, 52.9% higher) the peak plasma concentration of paclitaxel. Consequently, the absolute bioavailability of paclitaxel was increased by silibinin compared to that in the control group, and the relative bioavailability of oral paclitaxel was increased 1.15- to 2.02-fold. The intravenous pharmacokinetics of paclitaxel were not affected by the concurrent use of silibinin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability in the presence of silibinin could mainly be due to the increased intestinal absorption of paclitaxel via P-gp inhibition.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Interações Ervas-Drogas , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Silimarina/farmacologia , Administração Oral , Animais , Antineoplásicos Fitogênicos/sangue , Disponibilidade Biológica , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Paclitaxel/sangue , Ratos , Ratos Sprague-Dawley , Silibina
14.
Int J Pharm ; 337(1-2): 188-93, 2007 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-17267149

RESUMO

As many anticancer agents paclitaxel is a substrate for ATP-binding cassette (ABC) transporters such as P-glycoprotein-mediated efflux, and its metabolism in humans mainly catalyzed by CYP 3A4 and 2C8. Genistein, an isoflavonoid, is supposed to be an inhibitor of some ABC transporters, and its oxidative metobolism catalyzed by CYP 3A4 and 2C8. The purpose of this study was to investigate the effect of orally administered genistein on the pharmacokinetics of paclitaxel administered through oral and intravenous (i.v.) route in rats. A single dose of paclitaxel administered orally (30 mg/kg) or i.v. (3mg/kg) alone or 30 min after oral administration of genistein (3.3mg/kg or 10mg/kg). The presence of 10mg/kg genistein significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC, 54.7% greater) of orally administered paclitaxel, which was due to the significantly (p<0.05) decreased total plasma clearance (CL/F) of paclitaxel (35.2% lower). Genistein also increased the peak concentration (C(max)) of paclitaxel significantly (p<0.05 by 3.3mg/kg, 66.8% higher; p<0.01 by 10mg/kg, 91.8% higher). Consequently, the absolute bioavailability (F) of paclitaxel in the presence of genistein was 0.020-0.025, which was elevated more than the control group (0.016); and the relative bioavailability (Fr) of orally administered paclitaxel was increased from 1.26- to 1.55-fold. Ten milligrams per kilogram genistein also significantly (p<0.05) increased the AUC (40.5% greater) and reduced the total clearance (CLt, 30% lower) of i.v. administered paclitaxel. The presence of genistein improved the systemic exposure of paclitaxel in this study. The pharmacokinetic interaction between them should be taken into consideration when paclitaxel is used with genistein or the dietary supplements full of genistein.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Genisteína/farmacologia , Interações Ervas-Drogas , Medicamentos sem Prescrição , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Fitoestrógenos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Animais , Antineoplásicos Fitogênicos/sangue , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/metabolismo , Disponibilidade Biológica , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Genisteína/administração & dosagem , Genisteína/metabolismo , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Paclitaxel/sangue , Fitoestrógenos/administração & dosagem , Fitoestrógenos/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Arch Pharm Res ; 28(4): 469-75, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15918522

RESUMO

The purpose of this study was to investigate the effect of a cotreatment of bamboo concentrates (Jukcho solution; 0.75, 1.5, and 3.0 mL/kg) with the chemotherapeutic agent paclitaxel on the bioavailability of orally administered paclitaxel (50 mg/kg) in rats. The effect of a pretreatment of bamboo concentrates (1.5 and 3.0 mL/kg for 1.0 h or a consecutive 3 day) was also examined. The paclitaxel plasma concentrations of rats orally administered paclitaxel plus bamboo concentrates (coadministration, 3.0 mL/kg and pretreatment, 1.5 and 3.0 mL/kg) were significantly higher than those of rats treated with paclitaxel alone. Plasma concentrations of paclitaxel in groups pretreated with bamboo concentrates for 3 day were markedly higher than those of a paclitaxel control group at the measured time points. The areas under plasma concentration-time curves (AUCs) of paclitaxel in groups pretreated with bamboo concentrates were elevated and the absolute bioavailability (AB%) and relative bioavailability (RB%) of paclitaxel were also significantly higher than those in the control group. The peak concentration (Cmax), half-life (t1/2), and the elimination rate constant (Kel) of paclitaxel after 3 day of pretreatment with bamboo concentrates were also significantly higher than those in the control, but the time required to reach the maximum plasma concentration (Tmax) of paclitaxel was unaffected by the bamboo concentrates. Western blot analyses demonstrated that the level of CYP3A4 was increased in the livers of rats treated orally with paclitaxel, but this was reversed by pretreating with bamboo concentrates. These results show that bamboo concentrates enhance the bioavailability of orally administered paclitaxel and this effect may be associated with a diminished expression of CYP3A4 in the liver.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Inibidores Enzimáticos/farmacologia , Paclitaxel/farmacocinética , Extratos Vegetais/farmacologia , Sasa/química , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/sangue , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/biossíntese , Inibidores Enzimáticos/administração & dosagem , Immunoblotting , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Paclitaxel/administração & dosagem , Paclitaxel/sangue , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley
16.
Int J Pharm ; 292(1-2): 149-56, 2005 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-15725561

RESUMO

The aim of this study was to investigate the effect of naringin on the bioavailability and pharmacokinetics of paclitaxel after oral administration of paclitaxel or its prodrug coadministered with naringin to rats. Paclitaxel (40 mg/kg) and prodrug (280, 40 mg/kg paclitaxel equivalent) were coadministered orally to rats with naringin (1, 3, 10 and 20 mg/kg). The plasma concentrations of paclitaxel coadministered with naringin increased significantly (p<0.01 at paclitaxel, p<0.05 at prodrug) compared to the control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (C(max)) of paclitaxel with naringin significantly higher (p<0.01) than the control. The half-life (t(1/2)) was significantly (p<0.05) longer than the control. The absolute bioavailability (AB, %) of paclitaxel with naringin was significantly higher (3.5-6.8%, p<0.01) than the control (2.2%). Absorption rate constant (K(a)) of paclitaxel with naringin increased, but not significantly. The AUC of paclitaxel after coadministration of prodrug with naringin to rats was significantly (p<0.05) higher than the prodrug control. The relative bioavailability (RB, %) of paclitaxel after coadministration of prodrug with naringin was 1.35-1.69-fold higher than prodrug control. The absolute bioavailability (AB, %) of paclitaxel after coadministration of prodrug with naringin increased significantly (p<0.05) from 6.6 to 9.0% and 11.2%. The bioavailability of paclitaxel coadministered as a prodrug with or without naringin was remarkably higher than the control. Paclitaxel prodrug, a water-soluble compound concerning with its physicochemical properties, passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. Oral paclitaxel preparations which is more convenient than the IV dosage forms could be developed with a prodrug form with naringin.


Assuntos
Combinação de Medicamentos , Sinergismo Farmacológico , Flavanonas/farmacocinética , Paclitaxel/farmacocinética , Pró-Fármacos/farmacocinética , Absorção , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Avaliação Pré-Clínica de Medicamentos/métodos , Flavanonas/administração & dosagem , Meia-Vida , Masculino , Peso Molecular , Paclitaxel/análogos & derivados , Paclitaxel/sangue , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Solubilidade , Suspensões , Tecnologia Farmacêutica/métodos
17.
Circulation ; 110(7): 810-4, 2004 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-15302790

RESUMO

BACKGROUND: Drug-eluting stents have shown promising antirestenotic effects in clinical trials. Non-stent-based local delivery of antiproliferative drugs may offer additional flexibility and also reach vessel areas beyond the immediate stent coverage. The aim of the present study was to evaluate a novel method of local drug delivery based on angioplasty balloons. METHODS AND RESULTS: Stainless steel stents (n=40; diameter, 3.0 to 3.5 mm; length, 18 mm) were implanted in the left anterior descending and circumflex coronary arteries of domestic pigs. Both conventional uncoated and 3 different types of paclitaxel-coated, percutaneous transluminal coronary angioplasty balloons (contact with vessel wall for 1 minute) were used. No difference in short-term tolerance between coated and uncoated balloons and no signs of thrombotic events were observed. Quantitative angiography and histomorphometry of the stented arteries asserted the statistical equality of the baseline parameters between the control and the 3 treatment groups. Paclitaxel balloon coating led to a marked, dose-dependent reduction of parameters characterizing in-stent restenosis (reduction of neointimal area up to 63%). Despite the marked reduction in neointimal proliferation, endothelialization of stent struts was present in all samples. There was no evidence of a significant inflammatory response in the neighborhood of the stent struts. CONCLUSIONS: Paclitaxel balloon coating is safe, and it effectively inhibits restenosis after coronary angioplasty with stent implantation in the porcine model. The degree of reduction in neointimal formation was comparable to that achieved with drug-eluting stents.


Assuntos
Angioplastia Coronária com Balão/instrumentação , Reestenose Coronária/prevenção & controle , Estenose Coronária/terapia , Paclitaxel/administração & dosagem , Angioplastia Coronária com Balão/métodos , Animais , Vasos Coronários/química , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Avaliação Pré-Clínica de Medicamentos , Paclitaxel/sangue , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Stents , Sus scrofa , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/ultraestrutura
18.
J Thorac Cardiovasc Surg ; 123(4): 686-94, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11986596

RESUMO

OBJECTIVE: Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. METHODS: Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. RESULTS: Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5- to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. CONCLUSIONS: These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/sangue , Área Sob a Curva , Brônquios/citologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Humanos , Hipertermia Induzida/efeitos adversos , Infusões Intravenosas , Neoplasias Pulmonares/sangue , Paclitaxel/sangue , Ovinos , Resultado do Tratamento , Células Tumorais Cultivadas/efeitos dos fármacos
19.
Life Sci ; 53(12): PL183-7, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8103185

RESUMO

A mouse monoclonal anti-taxol antibody (69E4A8E) and a rabbit polyclonal anti-taxol antiserum were used to measure taxol levels in plant extracts in a double-blind experiment in conjunction with assays by HPLC. 69E4A8E was previously shown by ELISA to be specific for taxol with only a slight cross reaction with another bioactive compound, cephalomannine; the antiserum, on the other hand, was, by radioimmunoassay (RIA), essentially equally reactive with taxol and cephalomannine. Immunoassays of the plant extracts gave results in agreement with that found by HPLC, suggesting that the antibodies can be used in simple routine procedures for the quantification of taxol or taxol-like compounds in extracts of plants or other potential natural sources.


Assuntos
Antineoplásicos Fitogênicos/análise , Paclitaxel/análogos & derivados , Paclitaxel/análise , Taxoides , Animais , Anticorpos Monoclonais , Cromatografia Líquida de Alta Pressão , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Paclitaxel/sangue , Extratos Vegetais/química , Coelhos , Radioimunoensaio
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