Farmacogenómica: la medicina personalizada / Pharmacogenomic: the personalized medicine

El principal objetivo de la farmacogenómica (PGx) es definir un tratamiento farmacológico individualizado basado en el perfil genético de cada paciente, convirtiendo el paradigma clásico de tratamiento clínico centrado en la enfermedad en un nuevo enfoque, la medicina personalizada. Los polimorfismos genéticos pueden modificar la expresión y la función de las enzimas y las proteínas involucradas en la farmacocinética y la farmacodinámica de los fármacos. Así, la presencia de variantes alélicas permite predecir la respuesta farmacológica para garantizar la eficacia y la seguridad del tratamiento. Para la aplicación clínica de la PGx mediante la identificación de dichas variantes existen actualmente 2 planteamientos diferentes: el análisis de genes candidatos y los estudios de asociación genómica. La implementación clínica de la PGx mejora la eficacia, la seguridad y la relación costo-efectividad de los tratamientos; sin embargo, se ha ralentizado debido a una serie de barreras que se revisarán en este trabajo, así como sus posibles soluciones

The main objective of pharmacogenomics (PGx) is defining an individualized pharmacological treatment based on the genetic profile of each patient. Thus, the classical paradigm of clinical treatment focused on the disease is becoming a new approach, Personalized Medicine. The expression and function of enzymes and proteins involved in the drug pharmacokinetics and pharmacodynamics can be modified by genetic polymorphisms. Thereby, the presence of allelic variants allows predicting the pharmacological response guaranteeing the treatment efficacy and safety. Nowadays, two different approaches have been described for the clinical application of PGx by these variants identification: candidate gene analysis and genome wide association studies. Despite improving the effectiveness, safety and cost-effectiveness of treatments, the PGx clinical implementation has slowed down due to a series of barriers that will be reviewed in this work, as well as their possible solutions

Therapeutic hypothermia-induced pharmacokinetic alterations on CYP2E1 chlorzoxazone-mediated metabolism in a cardiac arrest rat model.

OBJECTIVES: Therapeutic hypothermia has demonstrated considerable benefit in patients experiencing cardiac arrest. Despite increasing clinical use, there is a paucity of information regarding the effect of hypothermia on the disposition of medications, specifically cytochrome P450-mediated drug metabolism. The objective was to determine the effect of hypothermia after cardiac arrest on the in vivo kinetics of a cytochrome P450 (CYP2E1) probe drug, chlorzoxazone, and to investigate the mechanism of these alterations. DESIGN: Laboratory investigation. SETTING: University pharmacy school and animal research facility. SUBJECTS: Sixteen male Sprague-Dawley rats. INTERVENTIONS: An asphyxial arrest rat model was used and moderate hypothermia was induced immediately postinsult via surface cooling. Chlorzoxazone was administered as an intravenous bolus, and plasma concentrations were analyzed using high-performance liquid chromatography methods. Protein binding was analyzed using rat control plasma, and Michaelis-Menten enzyme kinetic analysis was performed at 37 degrees C and 30 degrees C using control rat microsomes at varying concentrations of chlorzoxazone. MEASUREMENTS AND MAIN RESULTS: Moderate hypothermia after cardiac arrest in rats markedly decreased the systemic clearance of the CYP2E1 substrate, chlorzoxazone, when compared with normothermia after cardiac arrest, 1.26+/-0.34 mL/min vs. 0.580+/-0.37 mL/min (p<.001). No changes in chlorzoxazone protein binding were observed at 37 degrees C and 30 degrees C, and CYP2E1 enzyme capacity (maximum velocity) was not altered at these different incubation temperatures. However, Michaelis-Menten constant was significantly increased at 30 degrees C (551+/-150 microM) compared with incubations at 37 degrees C (255+/-52 microM, p<.01). CONCLUSIONS: Moderate hypothermia markedly reduces the systemic clearance of chlorzoxazone in cardiac arrest rats. This results from hypothermia-induced decreases in the CYP2E1 enzyme affinity for the substrate chlorzoxazone. This is the first systematic mechanistic investigation of the effect of hypothermia on CYP2E1-mediated metabolism.

Distribution of cytochrome P450 2C, 2E1, 3A4, and 3A5 in human colon mucosa.

BACKGROUND: Despite the fact that the alimentary tract is part of the body's first line of defense against orally ingested xenobiotica, little is known about the distribution and expression of cytochrome P450 (CYP) enzymes in human colon. Therefore, expression and protein levels of four representative CYPs (CYP2C(8), CYP2E1, CYP3A4, and CYP3A5) were determined in human colon mucosa biopsies obtained from ascending, descending and sigmoid colon. METHODS: Expression of CYP2C, CYP2E1, CYP3A4, and CYP3A5 mRNA in colon mucosa was determined by RT-PCR. Protein concentration of CYPs was determined using Western blot methods. RESULTS: Extensive interindividual variability was found for the expression of most of the genes. However, expression of CYP2C mRNA levels were significantly higher in the ascending colon than in the sigmoid colon. In contrast, mRNA levels of CYP2E1 and CYP3A5 were significantly lower in the ascending colon in comparison to the descending and sigmoid colon. In sigmoid colon protein levels of CYP2C8 were significantly higher by ~73% than in the descending colon. In contrast, protein concentration of CYP2E1 was significantly lower by ~81% in the sigmoid colon in comparison to the descending colon. CONCLUSION: The current data suggest that the expression of CYP2C, CYP2E1, and CYP3A5 varies in different parts of the colon.