Marked impact of P-glycoprotein on the absorption of TAK-427 in rats.
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.
Takeuchi
Toshiyuki
T
Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, Japan.
Nonaka
Masami
M
Yoshitomi
Sumie
S
Higuchi
Tomoaki
T
Ebihara
Takuya
T
Maeshiba
Yoshihiro
Y
Kawase
Masahiro
M
Asahi
Satoru
S
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D010539:Permeability; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007093:Imidazoles; D011724:Pyridazines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C469683:2-(6-((3-(4-(diphenylmethoxy)piperidino)propyl)amino)imidazo(1,2-b)pyridazin-2-yl)-2-methylpropionic acid; C095122:multidrug resistance protein 3