Effect of pluronic F68 block copolymer on P-glycoprotein transport and CYP3A4 metabolism

The aim of this work was to investigate the effects of pluronic F68 block copolymer on the P-gp-mediated transport of celiprolol (CEL) and CYP3A4-mediated formation of midazolam (MDZ) metabolite 1′-hydroxymidazolam. Over a range from 0.03 to 0.3%, pluronic F68 increased apical-to-basolateral permeab...

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Veröffentlicht in:International journal of pharmaceutics 2008-05, Vol.356 (1), p.351-353
Hauptverfasser: Huang, Jiangeng, Si, Luqin, Jiang, Lingli, Fan, Zhaoze, Qiu, Jun, Li, Gao
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Sprache:eng
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Zusammenfassung:The aim of this work was to investigate the effects of pluronic F68 block copolymer on the P-gp-mediated transport of celiprolol (CEL) and CYP3A4-mediated formation of midazolam (MDZ) metabolite 1′-hydroxymidazolam. Over a range from 0.03 to 0.3%, pluronic F68 increased apical-to-basolateral permeability (AP-BL) and decreased basolateral-to-apical permeability (BL-AP) of the P-gp substrate CEL in Caco-2 cell monolayer with the efflux ratio values of 2.8 ± 0.3 (0.03%), 2.6 ± 0.3 (0.1%), 2.3 ± 0.2 (0.3%), respectively. CEL transport across the intestinal mucosa in the everted gut sac model was also enhanced by the P-gp inhibitor verapamil and the pharmaceutical excipient pluronic F68. Furthermore, CYP3A4-catalyzed formation of 1′-hydroxymidazolam was inhibited by pluronic F68 with IC 50 and K i values of 0.11 and 0.16 mg/ml, respectively. The results indicate that pluronic F68 is a potent in vitro inhibitor of both P-gp and CYP3A4, suggesting a potential for pluronic F68 to modify the pharmacokinetics of orally administered drugs that are P-gp and/or CYP3A4 substrates in vivo.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2007.12.028