Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application of mdr1a knockout (-/-) rats into absorption study of multiple transporter substrate.

1.  This study was aimed to characterize gastrointestinal absorption of digoxin using wild-type (WT) and multidrug resistance protein 1a [mdr1a; P-glycoprotein (P-gp)] knockout (-/-) rats. 2.  In WT rats, the area under the plasma concentration-time curve (AUC) of oral digoxin increased after oral pretreatment with quinidine at 30 mg/kg compared with non-treatment, but the increasing ratio tended to decrease at a high dose of 100 mg/kg. In mdr1a (-/-) rats, however, quinidine pretreatment caused a dose-dependent decrease in the AUC. 3.  Quinidine pretreatment did not alter the hepatic availability of digoxin, indicating that the changes in the digoxin AUC were attributable to inhibition of the absorption process by quinidine; i.e. inhibition of influx by quinidine in mdr1a (-/-) rats and inhibition of efflux and influx by quinidine in WT rats. 4.  An in situ rat intestinal closed loop study using naringin implied that organic anion transporting peptide (Oatp) 1a5 may be a responsible transporter in the absorption of digoxin. 5.  These findings imply that the rat absorption behavior of digoxin is possibly governed by Oatp1a5-mediated influx and P-gp-mediated efflux. The mdr1a (-/-) rat is therefore a useful in vivo tool to investigate drug absorption associated with multiple transporters including P-gp.