RESUMO

The purpose of this study was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model linking etoposide free tumor and total plasma concentrations to the inhibition of solid tumor growth in rats. Walker-256 tumor cells were inoculated subcutaneously in the right flank of Wistar rats, which were randomly divided in control and two treated groups that received etoposide 5 or 10mg/kg i.v. bolus every day for 8 and 4days, respectively, and tumor volume was monitored daily for 30days. The plasma and intratumoral concentrations-time profiles were obtained from a previous study and were modeled by a four-compartment population pharmacokinetic (popPK) model. PK/PD analysis was conducted using MONOLIX v.4.3.3 on average data and by mean of a nonlinear mixed-effect model. PK/PD data were analyzed using a modification of Simeoni Tumor Growth Inhibition (TGI) model by introduction of an Emax function to take into account the concentration dependency of k2variable parameter (variable potency). The Simeoni TGI-Emax model was capable to fit schedule-dependent antitumor effects using the tumor growth curves from the control and two different administered schedules. The PK/PD model was capable of describing the tumor growth inhibition using total plasma or free tumor concentrations, resulting in higher k2max (maximal potency) for free concentrations (25.8mL·µg-1·day-1 - intratumoral vs. 12.6mL·µg-1·day-1 total plasma). These findings indicate that the plasma concentration may not be a good surrogate for pharmacologically active free tumor concentrations, emphasizing the importance of knowing drug tumor penetration to choose the best antitumor therapy.

Assuntos

RESUMO

Chemical composition of essential oils from four Stenachaenium species from South Brazil were established by gas chromatography coupled with mass spectrometry (GC/MS). The major compounds identified in the oil of S. megapotamicum were a coumarin derivative, 2H-1-benzopyran-2-one,7-(3-methylbutoxy) (24.0 percent), beta-bisabolene (12.8 percent) and thymol methyl ether (7.1 percent). The oil of S. adenanthum contained mainly pogostol (14.0 percent). S. riedelli oil showed significant presence of aliphatic compounds, with predominance of hexadecanoic acid in all samples (leaves, inflorescence and leaves collected during of inflorescence period). Hexadecanoic acid (23.8 percent) was also the main component in S. macrocephalum. Concerning antichemotactic activity, all the oil samples tested showed a significant leukocyte migration inhibition compared to chemotactic stimulant (lipopolysaccharide from Escherichia coli - LPS), at concentrations of 1 to 5 μg/mL, except for S. adenanthum. These results suggest that the essential oils of some Stenachaenium species could inhibit acute inflammatory process, because the migration of neutrophils occurs mainly in the early inflammatory process.

Se estableció la composición química de los aceites esenciales de cuatro especies de Stenachaenium del Sur de Brasil mediante cromatografía de gases acoplada a espectrometría de masas (CG/EM). Los compuestos mayoritarios identificados en el aceite de S. megapotamicum fueron: un derivado de cumarina, 2H-1-benzopiran-2-ona,7- (3-metilbutoxi) (24,0 por ciento), beta-bisaboleno (12,8 por ciento) y éter metil timol (7,1 por ciento). El aceite de S. adenanthum presentó principalmente pogostol (14,0 por ciento). El aceite de S. riedelli mostró una significativa presencia de compuestos alifáticos, con predominio de ácido hexadecanoico en todas las muestras (hojas, inflorescencias y hojas recolectadas durante del período de la inflorescencia). También el ácido hexadecanoico (23,8 por ciento) fue el principal componente en S. macrocephalum. En cuanto a la actividad antichemotaxica, todas las muestras de aceites ensayadas a concentraciones de 1 a 5 μg/ml, excepto para S. adenanthum, mostraron una inhibición significativa en la migración de leucocitos en comparación con agente quimiotáctico (lipopolisacárido de Escherichia coli – LPS). Estos resultados sugieren que los aceites esenciales provenientes de diferentes especies de Stenachaenium podrían inhibir procesos inflamatorios agudos, debido a que la migración de los neutrófilos se produce principalmente en el proceso inflamatorio temprano.

Assuntos