Influencia de la Glicoproteína-P, la CYP3A4 y las propiedades moleculares sobre la biodisponibilidad de los fármacos
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Fecha
2007-07-25
Autores
Sotolongo Reyes, Fran
Miranda Viña, Yasneisys
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Editor
Universidad Central "Marta Abreu" de Las Villas
Resumen
El citocromo P450 (CYP3A4) y la Glicoproteína P (P-gp) están presentes en altos niveles, en el enterocito intestinal. Esto sugiere que la biodisponibilidad de compuestos que son sustratos de la CYP3A4 y la P-gp pudiera ser reducida. Para estudiar esta relación se colectaron 300 compuestos sustratos y no sustratos de la CYP3A4 y la P-gp o de una de los dos y con valores de biodisponibilidad en humanos reportados y se calcularon diferentes propiedades moleculares
como el peso molecular, el área superficial polar, el coeficiente de partición, la polarizabilidad, la refractividad molar, el índice de insaturación y el factor hidrofílico. Se aplicó un Árbol de Clasificación para encontrar una regla que permitiera identificar los compuestos que eran sustratos de la P-gp y de la CYP3A4 (clase 1) del resto (clase 2). El modelo identificó el 87.72% de los compuestos en la clase 1 y el 81.89% de los de clase 2, para una clasificación total de 83%.
La calidad del modelo se corroboró mediante un estudio de validación cruzada y un set externo de 11 compuestos que eran sustratos de la CYP3A4 y de la P-gp, para un 79.66% y 90.0% de buena clasificación, respectivamente. Finalmente se realizó un “screening” virtual en 210 compuestos con valores reportados de absorción intestinal y biodisponibilidad en humanos.
Cincuenta y tres compuestos fueron identificados como potenciales sustratos de la CYP3A4 y la P-gp, y un 66.0% de ellos tuvieron valores de biodisponibilidad igual o menor que 60. Estos resultados sugieren que la presente regla pudiera ayudar a los químicos sintéticos a planificar la síntesis de compuestos, enfocados en la obtención de una incrementada probabilidad de buenos valores de biodisponibilidad, siendo una herramienta útil durante el proceso de descubrimiento de fármacos.
Cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp) are present, at high levels, in the small intestine enterocytes. This suggests that bioavailability of Pgp-CYP3A4 substrates can be reduced by both processes. To study this relationship were used 300 substrates and nonsubstrates of P-gp and CYP3A4, with human bioavailability values reported and different molecular properties such as: molecular weight, polar surface area, partition coefficient, polarizability, molar refractivity, unsaturation index and the hydrophilic factor were calculated. A Classification Tree Analysis was applied to find a simple hierarchical rule to identify Pgp-CYP3A4 substrates (class 1) from the rest of compounds (class 2). The model identified 87.72% of compounds in class 1 and 81.89% for class 2, for a general accuracy of 83.0%. The quality of the model was validated by a cross-validation procedure and an external set of 11 Pgp-CYP3A4 substrates for 79.66% and 90.9% of good prediction, respectively. Finally, a virtual screening of 210 compounds with human intestinal absorption and bioavailability values was developed. Fifty-three compounds were identified as potential Pgp-CYP3A4 substrates, and 66.0% of them had bioavailability values equal to or less than 60. This suggests that previous rule may help chemist to planning the synthesis focused on compounds with increased probability of oral bioavailability, being a useful tool during the drug discovery process.
Cytochrome P450 (CYP3A4) and P-glycoprotein (P-gp) are present, at high levels, in the small intestine enterocytes. This suggests that bioavailability of Pgp-CYP3A4 substrates can be reduced by both processes. To study this relationship were used 300 substrates and nonsubstrates of P-gp and CYP3A4, with human bioavailability values reported and different molecular properties such as: molecular weight, polar surface area, partition coefficient, polarizability, molar refractivity, unsaturation index and the hydrophilic factor were calculated. A Classification Tree Analysis was applied to find a simple hierarchical rule to identify Pgp-CYP3A4 substrates (class 1) from the rest of compounds (class 2). The model identified 87.72% of compounds in class 1 and 81.89% for class 2, for a general accuracy of 83.0%. The quality of the model was validated by a cross-validation procedure and an external set of 11 Pgp-CYP3A4 substrates for 79.66% and 90.9% of good prediction, respectively. Finally, a virtual screening of 210 compounds with human intestinal absorption and bioavailability values was developed. Fifty-three compounds were identified as potential Pgp-CYP3A4 substrates, and 66.0% of them had bioavailability values equal to or less than 60. This suggests that previous rule may help chemist to planning the synthesis focused on compounds with increased probability of oral bioavailability, being a useful tool during the drug discovery process.
Descripción
Palabras clave
Preparaciones Farmacéuticas, Pharmaceutical Preparations, Enterocytes, Mucosa Intestinal, Intestinal Mucosa, Enterocitos/química, Enterocytes/chemistry, Descubrimiento de Drogas, Drug Discovery