Reversible and time-dependent inhibition of CYP3A4-mediated nifedipine oxidation by noscapine

Substrate-dependent inhibition of CYP3A4 might influence the extrapolation of drug interactions from the in vitro to in vivo situation. The aim of the present study is to investigate reversible and time-dependent inhibition of CYP3A4-mediated nifedipine oxidation by noscapine. Furthermore, in vitroi...

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Detalles Bibliográficos
Autores principales: Wang, Li-Ming, Yang, Ling, Li, Ming, Sun, De-Guang, Tang, Bo, Gao, Zhen-Ming, Liang, Rui, Qu, Yan-Qing, Fang, Zhong-Ze, Tang, Shu-Hong, Jin, Xue Li
Formato: Articulo Comunicacion
Lenguaje:Inglés
Publicado: 2011
Materias:
Farmacia
Warfarina
Sustratos
Noscapina
Nifedipino
Interacciones de Drogas
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/8385
http://www.latamjpharm.org/resumenes/30/9/LAJOP_30_9_2_2.pdf
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
Descripción
Sumario:Substrate-dependent inhibition of CYP3A4 might influence the extrapolation of drug interactions from the in vitro to in vivo situation. The aim of the present study is to investigate reversible and time-dependent inhibition of CYP3A4-mediated nifedipine oxidation by noscapine. Furthermore, in vitroin vivo extrapolation (IVIVE) was performed using in vitro parameters. The results showed that CYP3A4- mediated nifedipine oxidation activity was strongly inhibited with an IC<sub>50</sub> of 25.7 ± 5.4 μM. Kinetic analysis showed that inhibition of CYP3A4-mediated nifedipine oxidation by noscapine was best fit to a noncompetitive manner with Ki value of 10.9 μM. IC50 shift experiment showed that IC50 was significantly decreased from 25.7 ± 5.4 μM to 0.34 ± 0.07 μM after pre-incubation with noscapine for 30 min, which indicated that time-dependent inhibition existed for inhibition of CYP3A4 by noscapine. The AUC of (R)- warfarin was predicted to increase by 0.5 % using C<sub>max</sub> or 0.2 % using unbound C<sub>max</sub> with reversible inhibition prediction equation, while the AUC of (R)-warfarin was estimated to increase by 23.1 % using C<sub>max</sub> or 10.4 % using unbound C<sub>max</sub> with TDI prediction equation. Inhibition of CYP3A4 by noscapine showed substrate-dependent inhibition behaviour. However, the results obtained from IVIVE are very similar using testosterone or nifedipine as probe substrates.

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