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Separación de las acciones basadas en el mecanismo y fuera del objetivo de los inhibidores de la proteína de
Reecha Sofat1, Aroon D Hingorani, Liam Smeeth
1Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom.
Circulation
|December 23, 2009
Resumen
Los inhibidores de la proteína de transferencia del éster de colesterol (CETP) afectan el colesterol HDL, pero el torcetrapib causó presión arterial alta. El análisis genético reveló torcetrapib.
Área de la Ciencia:
- La farmacogenómica es la farmacogenómica.
- Medicina Cardiovascular La medicina cardiovascular es una especialidad de la salud.
- El metabolismo de los lípidos.
Sus antecedentes:
- Los inhibidores de la proteína de transferencia del éster de colesterol (CETP) aumentan el colesterol HDL.
- El torcetrapib, un inhibidor de la CETP, aumentó inesperadamente la presión arterial y los eventos cardiovasculares.
- Se debatió la causa del efecto hipertensivo del torcetrapib (inhibición de la CETP frente a la acción fuera del objetivo).
Objetivo del estudio:
- Para determinar si los polimorfismos de un solo nucleótido (SNPs) del gen CETP podrían diferenciar los efectos basados en el mecanismo de los efectos fuera del objetivo de los inhibidores de CETP.
- Validar la CETP como un objetivo terapéutico mediante el análisis genético frente a los efectos de los medicamentos.
Principales métodos:
- Efectos comparados de los SNPs de CETP y el torcetrapib en los lípidos, la presión arterial y los electrolitos.
- Se utilizaron datos de estudios genéticos (67.687 individuos) y ensayos aleatorizados (17.911 participantes).
- Se analizaron las fracciones lipídicas, la presión arterial y los cambios en los electrolitos en relación con la actividad de la CETP.
Principales resultados:
- Tanto los SNPs de la CETP como el torcetrapib redujeron la actividad de la CETP y afectaron consistentemente 8 rasgos lipídicos, incluido el colesterol HDL.
- El torcetrapib (60 mg) elevó significativamente la presión arterial sistólica (4.47 mm Hg) y diastólica (2.08 mm Hg).
- Los SNPs de CETP tuvieron un efecto nulo en la presión arterial (sistólico: 0.16 mm Hg, diastólico: -0.04 mm Hg), que difiere significativamente del impacto de torcetrapib.
Conclusiones:
- La discordancia en los efectos de la presión arterial entre los SNPs de CETP y el torcetrapib sugiere que la hipertensión de torcetrapib no se debe a la inhibición de CETP.
- Es poco probable que la acción hipertensiva de Torcetrapib sea compartida por otros inhibidores de la CETP.
- Los estudios genéticos ofrecen una herramienta valiosa para el desarrollo de fármacos, proporcionando evidencia aleatoria para la validación del objetivo del fármaco en humanos.
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