Marked impact of P-glycoprotein on the absorption of TAK-427 in rats

Autor: Tomoaki Higuchi, Takuya Ebihara, Toshiyuki Takeuchi, Masahiro Kawase, Masami Nonaka, Sumie Yoshitomi, Satoru Asahi, Yoshihiro Maeshiba
Rok vydání: 2008
Předmět:
Zdroj: Biopharmaceutics & Drug Disposition. 29:311-323
ISSN: 1099-081X
0142-2782
DOI: 10.1002/bdd.609
Popis: The role of P-glycoprotein (P-gp, ABCB1) on the absorption process was investigated by drug–drug interaction studies of TAK-427 with P-gp inhibitors (erythromycin, ketoconazole or quinidine) in rats and by transport studies using rat multidrug resistance (MDR1) stably expressing cells and rat small intestine mounted in a Ussing-type chamber. TAK-427 showed high efflux activity with low permeability in rat MDR1a and MDR1b stably expressing cells and was revealed to be a typical substrate for P-gps. Although TAK-427 was mainly absorbed from the small intestine in rats, a large part of the dosed compound remained in the gastrointestinal tract. Orally co-administered P-gp inhibitors (50 mg/kg) increased the AUC of TAK-427 after a 5 mg/kg oral dose 5.4- to 18.3-fold, whereas orally administered P-gp inhibitors had a minor effect on the increase in the AUC of TAK-427 (1.3- to 2.2-fold) after a 0.5 mg/kg intravenous dose. Thus, the bioavailability of TAK-427 after oral administration in rats (7.3%) markedly increased when co-administered with P-gp inhibitors (28.6–57.6%). Moreover, the transport of TAK-427 was predominantly secretory throughout the rat small intestine and was inhibited by P-gp inhibitors. In conclusion, P-gp can markedly reduce the absorption of a typical P-gp substrate by its efflux activity throughout the absorption site. Copyright © 2008 John Wiley & Sons, Ltd.
Databáze: OpenAIRE
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