RESUMEN
Purpose: Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. Methods: We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. Results: In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. Conclusion: This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.
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Isoflavonas , Liposomas , Daño por Reperfusión Miocárdica , Compuestos Organofosforados , Animales , Liposomas/química , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Isoflavonas/química , Isoflavonas/farmacología , Isoflavonas/administración & dosificación , Isoflavonas/farmacocinética , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/farmacocinética , Masculino , Ratones , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Cationes/química , Miocardio/patología , Miocardio/metabolismo , Estrés Oxidativo/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Péptidos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodosRESUMEN
The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with ß-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.
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Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Naftoquinonas/administración & dosificación , Neoplasias/tratamiento farmacológico , Estrés Oxidativo , Profármacos/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Quitosano/administración & dosificación , Quitosano/química , Quitosano/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Mitocondrias/fisiología , Nanopartículas/química , Naftoquinonas/química , Naftoquinonas/farmacocinética , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Oxidación-Reducción , Profármacos/química , Profármacos/farmacocinética , Especies Reactivas de Oxígeno/metabolismo , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Carga Tumoral/efectos de los fármacosRESUMEN
The mitochondrion can be considered as the metabolic powerhouse of the cell, having a key impact on energy production, cell respiration, and intrinsic cell death. Mitochondria are also the main source of endogenous reactive oxygen species , including free radicals (FR), which are physiologically involved in signaling pathways but may promote cell damage when unregulated or excessively formed in inappropriate locations. A variety of chronic pathologies have been associated with FR-induced mitochondrial dysfunctions , such as cancer, age-related neurodegenerative diseases, and metabolic syndrome.In recent years drug design based on specific mitochondria-targeted antioxidants has become a very attractive therapeutic strategy and, among target compounds, nitrones have received growing attention because of their specific affinity toward FR. Here, we describe protocols dealing with the preparation, mitochondria permeation assessment, electron paramagnetic resonance (EPR) spin trapping setting, and antiapoptotic properties evaluation of a series of new linear nitrones vectorized by a triphenylphosphonium cation and labeled with a diethoxyphosphoryl moiety as 31P nuclear magnetic resonance (NMR) reporter with antioxidant property.
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Antioxidantes/síntesis química , Mitocondrias/química , Óxidos de Nitrógeno/química , Compuestos Organofosforados/síntesis química , Células 3T3 , Animales , Antioxidantes/química , Antioxidantes/farmacocinética , Espectroscopía de Resonancia por Spin del Electrón , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Estructura Molecular , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Isótopos de Fósforo/química , Fosforilación , Ratas , Detección de SpinRESUMEN
Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non-small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.
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Compuestos Organofosforados/farmacocinética , Pirimidinas/farmacocinética , Insuficiencia Renal/metabolismo , Anciano , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Área Bajo la Curva , Femenino , Tasa de Filtración Glomerular , Semivida , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Compuestos Organofosforados/sangre , Compuestos Organofosforados/orina , Gravedad del Paciente , Unión Proteica/fisiología , Pirimidinas/sangre , Pirimidinas/orinaRESUMEN
The synthesis of a new series of Gd(III)-arylphosphonium complexes is described and the solution stability of selected compounds is reported. Their lipophilicity and uptake in human glial (SVG p12) and human glioblastoma multiforme (T98G) cell lines are presented. The in vitro cytotoxicity of all complexes was determined to be low at therapeutically-relevant concentrations. Selected Gd(III) complexes are potential candidates for further investigation as theranostic agents.
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Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Gadolinio/química , Glioblastoma/tratamiento farmacológico , Compuestos Organofosforados/síntesis química , Compuestos Organofosforados/farmacología , Antineoplásicos/farmacocinética , Proliferación Celular , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Compuestos Organofosforados/farmacocinética , Distribución Tisular , Células Tumorales CultivadasRESUMEN
BACKGROUND AND OBJECTIVES: Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. METHODS: Plasma concentration-time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). RESULTS: Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. CONCLUSIONS: Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.
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Neoplasias , Compuestos Organofosforados , Pirimidinas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos como Asunto , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Compuestos Organofosforados/farmacocinética , Pirimidinas/farmacocinética , Adulto JovenRESUMEN
Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of 68Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent.
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Acetamidas/química , Huesos/diagnóstico por imagen , Compuestos Macrocíclicos/química , Compuestos Organofosforados/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Acetamidas/sangre , Acetamidas/farmacocinética , Radioisótopos de Galio , Humanos , Compuestos Macrocíclicos/sangre , Compuestos Macrocíclicos/farmacocinética , Estructura Molecular , Compuestos Organofosforados/sangre , Compuestos Organofosforados/farmacocinética , Radiofármacos/sangre , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
PURPOSE: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events). METHODS: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected. RESULTS: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69). CONCLUSION: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Crizotinib/efectos adversos , Crizotinib/sangre , Crizotinib/farmacocinética , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Compuestos Organofosforados/efectos adversos , Compuestos Organofosforados/sangre , Compuestos Organofosforados/farmacocinética , Supervivencia sin Progresión , Pirimidinas/efectos adversos , Pirimidinas/sangre , Pirimidinas/farmacocinética , Calidad de Vida , Tasa de Supervivencia , Adulto JovenRESUMEN
The aim of this present study was to investigate the ability of different dissolution methods to predict the in vivo performance of efonidipine hydrochloride (EFH). The solid dispersions of EFH were prepared by solvent evaporation method with HPMC-AS as matrix and urea as a pH adjusting agent. The paddle method, the open-loop, and the closed-loop flow-through cell methods were studied. In the study, Weibull's model was the best fit to explain release profiles. The pharmacokinetics behaviors of two kinds of solid dispersions with different release rate were investigated in comparison to the EFH after oral administration in rats. In vivo absorption was calculated by a numerical deconvolution method. In the study, the level A in vivo and in vitro correlation (IVIVC) was utilized. The correlation coefficient was calculated and interpreted by means of linear regression analysis (Origin.Pro.8.5 software). As a result, excellent IVIVC for solid dispersions and crude drug (r2 = 0.9352-0.9916) was obtained for the dissolution rate determined with flow-through cell open-loop system in phosphate buffer solution with 0.1% (w/v) polysorbate 80 at pH 6.5, the flow-rate of 4 mL/min. In addition, the self-assembled flow cell system had good repeatability and accuracy. The dissolution rate of the solid dispersion could be slowed down by the flow-through method, and the difference caused by preparation was significantly distinguished. The study demonstrated that flow-through cell method of the open-loop, compared with paddle method, was suitable for predicting in vivo performance of EFH solid dispersions.
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Bloqueadores de los Canales de Calcio/química , Dihidropiridinas/química , Nitrofenoles/química , Animales , Bloqueadores de los Canales de Calcio/farmacocinética , Dihidropiridinas/farmacocinética , Técnicas In Vitro , Masculino , Nitrofenoles/farmacocinética , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Preparaciones Farmacéuticas , Ratas , Ratas Sprague-Dawley , Solubilidad , Solventes , AguaRESUMEN
The strategy of using radioligands for targeting the prostate-specific membrane antigen (PSMA) revealed to be promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently developed albumin-binding PSMA radioligands showed a remarkably increased tumor uptake because of the enhanced blood circulation, but higher accumulation of activity was also observed in off-target organs and tissues. The aim of this study was to investigate the option of using fast-cleared, small-molecular-weight PSMA inhibitors (PSMA-11, 2-PMPA, and ZJ-43) to reduce the kidney uptake of [177Lu]Lu-PSMA-ALB-56, a previously developed albumin-binding PSMA radioligand. Dual-isotope SPECT/CT imaging was performed with tumor-bearing mice coinjected with [177Lu]Lu-PSMA-ALB-56 and a 2.5-fold molar excess of [67Ga]Ga-PSMA-11. At early timepoints after injection, the high renal uptake of [67Ga]Ga-PSMA-11 reduced the accumulation of [177Lu]Lu-PSMA-ALB-56 in the kidneys substantially, whereas the tumor uptake of [177Lu]Lu-PSMA-ALB-56 was only slightly affected. These findings were confirmed in biodistribution studies, which revealed reduced uptake of [177Lu]Lu-PSMA-ALB-56 in the kidneys due to coadministered unlabeled PSMA-11 (9.1 ± 0.8% IA/g vs 46 ± 11% IA/g; 1 h p.i.). The tumor uptake of [177Lu]Lu-PSMA-ALB-56 was almost the same at 1 h p.i., irrespective of whether or not PSMA-11 was coinjected (24 ± 6% IA/g vs 27 ± 7% IA/g). The application of [177Lu]Lu-PSMA-ALB-56 with 2-PMPA or ZJ-43, respectively, showed similar results in biodistribution studies. Among all three tested PSMA inhibitors, 2-PMPA, applied at a 2.5-fold molar excess relative to [177Lu]Lu-PSMA-ALB-56, was most effective to improve the tumor-to-kidney ratios over the first hours after injection of [177Lu]Lu-PSMA-ALB-56. The concept of using a PSMA inhibitor together with [177Lu]Lu-PSMA-ALB-56 appears promising in view of a clinical translation of this and possibly other long-circulating PSMA radioligands.
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Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Neoplasias de la Próstata/metabolismo , Animales , Línea Celular Tumoral , Humanos , Riñón/metabolismo , Masculino , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-ß-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).
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Antivirales/farmacología , Desoxiuridina/análogos & derivados , Desoxiuridina/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Profármacos/farmacología , Ácidos Aminoisobutíricos/metabolismo , Ácidos Aminoisobutíricos/farmacocinética , Ácidos Aminoisobutíricos/farmacología , Animales , Antivirales/metabolismo , Antivirales/farmacocinética , Desoxiuridina/metabolismo , Desoxiuridina/farmacocinética , Perros , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , Hepatocitos/metabolismo , Humanos , Hígado/metabolismo , Pruebas de Sensibilidad Microbiana , Compuestos Organofosforados/metabolismo , Compuestos Organofosforados/farmacocinética , Compuestos Organofosforados/farmacología , Profármacos/metabolismo , Profármacos/farmacocinética , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Replicación Viral/efectos de los fármacosRESUMEN
In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors.
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Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Compuestos Organofosforados/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Administración Oral , Adulto , Anciano , Quinasa de Linfoma Anaplásico/metabolismo , Área Bajo la Curva , Estudios Cruzados , Inductores del Citocromo P-450 CYP2B6/administración & dosificación , Inductores del Citocromo P-450 CYP2B6/farmacocinética , Citocromo P-450 CYP2C8/metabolismo , Inhibidores del Citocromo P-450 CYP2C8/administración & dosificación , Inhibidores del Citocromo P-450 CYP2C8/farmacocinética , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Gemfibrozilo/administración & dosificación , Gemfibrozilo/farmacocinética , Voluntarios Sanos , Humanos , Itraconazol/administración & dosificación , Itraconazol/farmacocinética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Compuestos Organofosforados/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Rifampin/administración & dosificación , Rifampin/farmacocinéticaRESUMEN
2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent (IC50 = 300 pM) and selective inhibitor of glutamate carboxypeptidase II (GCPII) with efficacy in multiple neurological and psychiatric disease preclinical models and more recently in models of inflammatory bowel disease (IBD) and cancer. 2-PMPA (1), however, has not been clinically developed due to its poor oral bioavailability (<1%) imparted by its four acidic functionalities (c Log P = -1.14). In an attempt to improve the oral bioavailability of 2-PMPA, we explored a prodrug approach using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL), an FDA-approved promoiety, and systematically masked two (2), three (3), or all four (4) of its acidic groups. The prodrugs were evaluated for in vitro stability and in vivo pharmacokinetics in mice and dog. Prodrugs 2, 3, and 4 were found to be moderately stable at pH 7.4 in phosphate-buffered saline (57, 63, and 54% remaining at 1 h, respectively), but rapidly hydrolyzed in plasma and liver microsomes, across species. In vivo, in a single time-point screening study in mice, 10 mg/kg 2-PMPA equivalent doses of 2, 3, and 4 delivered significantly higher 2-PMPA plasma concentrations (3.65 ± 0.37, 3.56 ± 0.46, and 17.3 ± 5.03 nmol/mL, respectively) versus 2-PMPA (0.25 ± 0.02 nmol/mL). Given that prodrug 4 delivered the highest 2-PMPA levels, we next evaluated it in an extended time-course pharmacokinetic study in mice. 4 demonstrated an 80-fold enhancement in exposure versus oral 2-PMPA (AUC0-t: 52.1 ± 5.9 versus 0.65 ± 0.13 h*nmol/mL) with a calculated absolute oral bioavailability of 50%. In mouse brain, 4 showed similar exposures to that achieved with the IV route (1.2 ± 0.2 versus 1.6 ± 0.2 h*nmol/g). Further, in dogs, relative to orally administered 2-PMPA, 4 delivered a 44-fold enhanced 2-PMPA plasma exposure (AUC0-t for 4: 62.6 h*nmol/mL versus AUC0-t for 2-PMPA: 1.44 h*nmol/mL). These results suggest that ODOL promoieties can serve as a promising strategy for enhancing the oral bioavailability of multiply charged compounds, such as 2-PMPA, and enable its clinical translation.
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Microsomas Hepáticos/metabolismo , Compuestos Organofosforados/metabolismo , Profármacos/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Perros , Masculino , Ratones , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Profármacos/administración & dosificación , Profármacos/química , Profármacos/farmacocinética , Distribución TisularRESUMEN
Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.
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Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Nanoconjugados/química , Compuestos Organofosforados/administración & dosificación , Acetales/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Composición de Medicamentos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Micelas , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Poliésteres/química , Polietilenglicoles/química , Distribución TisularRESUMEN
Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation PET tracers may be suitable for early detection of cardiotoxicity. This study aimed to evaluate an 18F-labeled lipophilic phosphonium cation, [1-(2-18F-fluoroethyl),1H[1,2,3]triazole-4-ethylene]triphenylphosphonium bromide (18F-MitoPhos), as a cardiac imaging agent, comparing it with leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin model. Methods: Cardiac uptake and response to decreased mitochondrial membrane potential of 18F-MitoPhos and 99mTc-sestamibi were tested in isolated perfused rat hearts. Baseline pharmacokinetic profiles of 18F-MitoPhos and 18F-fluorobenzyltriphenylphosphonium and their response to acute doxorubicin-induced cardiotoxicity were assessed in rats in vivo (10, 15, or 20 mg of doxorubicin per kilogram, intravenously, 48 h beforehand). Results: Cardiac retention of 18F-MitoPhos was more than double that of 99mTc-sestamibi in isolated perfused rat hearts. A favorable biodistribution of 18F-MitoPhos in vivo was observed, with heart-to-tissue ratios of 304 ± 186, 11.2 ± 1.2, and 3.8 ± 0.6 for plasma, liver, and lung, respectively (60 min). A significant dose-dependent loss of cardiac retention of 18F-MitoPhos was observed on doxorubicin treatment, with average cardiac SUV from 30 to 60 min (mean ± SD) decreasing from 3.5 ± 0.5 (control) to 1.8 ± 0.1 (doxorubicin, 20 mg/kg). Other assessed biomarkers showed no alterations. Conclusion:18F-MitoPhos showed pharmacokinetic parameters suitable for cardiac imaging. A significant dose response of cardiac uptake to doxorubicin treatment was observed before detectable biomarker alterations. 18F-MitoPhos is therefore a promising tracer for imaging chemotherapy-induced cardiotoxicity. To our knowledge, this is the first demonstration of radiolabeled lipophilic cations being used for the PET imaging of chemotherapy-induced cardiotoxicity and indicates the potential application of these compounds in this area.
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Antineoplásicos/efectos adversos , Cardiotoxicidad/diagnóstico por imagen , Radioisótopos de Flúor , Interacciones Hidrofóbicas e Hidrofílicas , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Tomografía de Emisión de Positrones , Animales , Cardiotoxicidad/etiología , Cardiotoxicidad/metabolismo , Doxorrubicina/efectos adversos , Marcaje Isotópico , Masculino , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Owing to its favorable radioactive decay characteristics (T1/2 = 32.51 d, Eß [max] = 434.6 keV [70.5%] and 580.0 keV [29.5%], Eγ = 145.4 keV [48.5%]), 141 Ce could be envisaged as a theranostic radionuclide for use in nuclear medicine. The present article reports synthesis and evaluation of 141 Ce complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (DOTMP) as a potent theranostic agent targeting metastatic skeletal lesions. Ce-141 was produced with 314 ± 29 MBq/mg (n = 6) specific activity and >99.9% radionuclidic purity (n = 6). Around 185 MBq dose of [141 Ce]Ce-DOTMP was synthesized with 98.6 ± 0.5% (n = 4) radiochemical yield under optimized conditions of reaction, and the preparation showed adequately high in vitro stability. Biodistribution studies in normal Wistar rats demonstrated significant skeletal localization and retention of injected activity (2.73 ± 0.28% and 2.63 ± 0.22% of injected activity per gram in femur at 3 hours and 14 days post-injection, respectively) with rapid clearance from non-target organs. The results of biodistribution studies were corroborated by serial scintigraphic imaging studies. These results demonstrate the potential utility of 141 Ce-DOTMP as a theranostic molecule for personalized patient care of cancer patients suffering from painful metastatic skeletal lesions.
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Neoplasias Óseas/complicaciones , Neoplasias Óseas/secundario , Dolor en Cáncer/diagnóstico por imagen , Dolor en Cáncer/radioterapia , Radioisótopos de Cerio/uso terapéutico , Compuestos Organofosforados/uso terapéutico , Adsorción , Animales , Dolor en Cáncer/etiología , Durapatita/química , Marcaje Isotópico , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Cintigrafía , Ratas , Ratas Wistar , Distribución TisularRESUMEN
Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48â¯h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity.
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Camptotecina/administración & dosificación , Quitosano/administración & dosificación , Reactivos de Enlaces Cruzados/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Compuestos Organofosforados/administración & dosificación , Administración Oral , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Células CACO-2 , Camptotecina/química , Camptotecina/farmacocinética , Quitosano/química , Quitosano/farmacocinética , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/farmacocinética , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacocinética , Masculino , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Ratas , Ratas WistarRESUMEN
The heart failure epidemic continues to rise with coronary artery disease as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 s), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed.
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Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Circulación Coronaria , Vasos Coronarios/diagnóstico por imagen , Imagen de Perfusión Miocárdica/métodos , Compuestos Organofosforados/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Piridazinas/administración & dosificación , Radiofármacos/administración & dosificación , Animales , Enfermedad de la Arteria Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Humanos , Imagen de Perfusión Miocárdica/tendencias , Compuestos Organofosforados/farmacocinética , Tomografía de Emisión de Positrones/tendencias , Valor Predictivo de las Pruebas , Piridazinas/farmacocinética , Radiofármacos/farmacocinéticaRESUMEN
The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.
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Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carbazoles/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Crizotinib/farmacocinética , Neoplasias Pulmonares/metabolismo , Compuestos Organofosforados/farmacocinética , Piperidinas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Sulfonas/farmacocinética , Animales , Interacciones Farmacológicas , Humanos , Proteínas de Transporte de Membrana/metabolismoRESUMEN
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment-emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high-fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.