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

• Published in: Biopharmaceutics & drug disposition Vol. 29; no. 6; pp. 311 - 323
• Main Authors: Takeuchi, Toshiyuki, Nonaka, Masami, Yoshitomi, Sumie, Higuchi, Tomoaki, Ebihara, Takuya, Maeshiba, Yoshihiro, Kawase, Masahiro, Asahi, Satoru
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.09.2008
• Subjects: ABCB1; absorption; Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP-Binding Cassette Sub-Family B Member 4; bioavailability; Biological Availability; Biological Transport; Cell Line; Dose-Response Relationship, Drug; Drug Interactions; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Intestine, Small - metabolism; Male; P-glycoprotein (P-gp; Permeability; Pyridazines - administration & dosage; Pyridazines - pharmacokinetics; P‐glycoprotein (P‐gp, ABCB1); rat; Rats; Rats, Sprague-Dawley; TAK-427
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.609

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.