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. (November 2014)

• Record Type: Journal Article
• Authors: Suzuki, Motoya; Komura, Hiroshi; Yoshikawa, Tomonori; Enya, Seiji; Nagao, Akemi; Takubo, Hiroaki; Kogayu, Motohiro
• Is Part Of: Xenobiotica. Volume 44:Number 11(2014:Nov.)
• Page Start: 1039
• Page End: 1045
• Publication Date: 2014-11
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.920551
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. <?ri?>This study was aimed to characterize gastrointestinal absorption of digoxin using wild-type (WT) and multidrug resistance protein 1a [<italic>mdr1a</italic>; P-glycoprotein (P-gp)] knockout (−/−) rats.</p> <p>2. <?ri?>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 <italic>mdr1a</italic> (−/−) rats, however, quinidine pretreatment caused a dose-dependent decrease in the AUC.</p> <p>3. <?ri?>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 <italic>mdr1a</italic> (−/−) rats and inhibition of efflux and influx by quinidine in WT rats.</p> <p>4. <?ri?>An <italic>in situ</italic> 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.</p> <p>5. <?ri?>These findings imply that the rat absorption behavior of digoxin is possibly governed by Oatp1a5-mediated influx and P-gp-mediated efflux. The <italic>mdr1a</italic> (−/−) rat is therefore a useful <italic>in vivo</italic> tool to investigate drug absorption associated with multiple transporters including P-gp.</p> </abstract>