@misc{10481/58343,
year = {2017},
month = {4},
url = {http://hdl.handle.net/10481/58343},
abstract = {Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation,
and cytochrome P450, the major enzymes involved in drug metabolism, share
striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated
biotransformations might play an important role in the pharmacological modulation
of nitric oxide synthase. In this work, we have undertaken an integrated in vitro
assessment of the hepatic metabolism and nitric oxide modulation of previously
described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess
the implication of CYP450 activities over production of nitric oxide. In vitro systems
based in human liver microsomes and activated mouse macrophages were developed
for these purposes. Additionally in vitro production the hepatic metabolites of dual
inhibitor, roxithromycin, was investigated achieving the identification and isolation of
main hepatic biotransformation products. Our results suggested that for some macrolide
compounds, the cytochrome P450 3A4 derived drug metabolites have an important
effect on nitric oxide production and might critically contribute to the pharmacological
immunomodulatory activity observed.},
organization = {This work was supported by the Spanish Ministry of Economy
and Competitivity (SAF2011-29648) and Junta de Andalucía
(AGR-6826 and CTS 164) with funds from the European
Union; FA is a predoctoral fellow of Junta de Andalucia;
MR is a postdoctoral fellow of CIBER-EHD. The CIBEREHD is funded by the Instituto de Salud Carlos III. The
MEDINA authors disclosed the receipt of financial support
from Fundación MEDINA, a public-private partnership of
Merck Sharp and Dohme de España S.A./Universidad de
Granada/Junta de Andalucía. In the case of Noemi Vergara
Segura, she was a CEIBioTic fellow from the program at
the Granada University. The results presented in this work
will be compiled in the doctoral thesis (knowledge area code
32089 and subject code 320903) entitled “Evaluación de la
actividad de los metabolitos hepáticos derivados de compuestos
inmunomodulares e inhibidores de GSK3,” carried out currently
by JP at FUNDACIÓN MEDINA in collaboration with the
department of Pharmacology at the University of Granada,
being the thesis directors, FV (FUNDACIÓN MEDINA) and JG
(Universidad de Granada).},
publisher = {Frontiers Media},
keywords = {Nitric oxide},
keywords = {Oxide CYP450},
keywords = {Drug metabolism},
keywords = {Immunomodulation},
title = {Exploring the Role of CYP3A4 Mediated Drug Metabolism in the Pharmacological Modulation of Nitric Oxide Production},
doi = {10.3389/fphar.2017.00202},
author = {Pérez del Palacio, José and Díaz, Caridad and Vergara, Noemi and Algieri, Francesca and Rodríguez-Nogales, Alba and De Pedro, Nuria and Rodríguez Cabezas, María Elena and Genilloud Rodríguez, Olga and Gálvez Peralta, Julio Juan and Vicente, Francisca},
}