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The complexity of intestinal absorption and exsorption of digoxin in rats.
Int J Pharm. 2006 Sep 28; 322(1-2):79-86.IJ

Abstract

The potential multiple carrier-mediated mechanisms involved in the transport of digoxin in rat intestine were investigated by the rapid filtration method in rat intestinal brush-border vesicles (BBMV) and in vitro Ussing chambers. The uptake of digoxin showed a typical overshoot phenomenon in the presence of an inward proton gradient and an outward bicarbonate gradient, or an outward glutathione gradient in BBMV. Good fitting to an equation consisting of both saturable and linear terms was obtained using non-linear regression analysis. GF120918, a specific P-gp inhibitor, significantly increased the absorptive permeability of digoxin in rat ileum (7.02 x 10(-7) cm/s versus 2.11 x 10(-6) cm/s with GF120918) but the addition of DIDS (0.5 mM), an anionic transporter inhibitor, or bromosulfophthalein (0.1 mM), an Oatp inhibitor, in the presence of GF120918 decreased the absorptive permeability compared with GF120918 alone (2.11 x 10(-6) cm/s versus 1.46 x 10(-6) cm/s, p<0.01 and 2.11 x 10(-6) cm/s versus 1.60 x 10(-6) cm/s, p<0.05, respectively). The above results suggest the involvement of carrier-mediated uptake mechanism, possibly Oatp, in digoxin absorption. Interestingly, GF120918 (1 microM) did not abolish the polarized transport of digoxin in rat jejunum and ileum, and DIDS (0.5 mM), not a P-gp inhibitor, and MK571 (50 microM), an MRP-selective inhibitor, can also significantly decrease the exsorptive permeability of digoxin. This result indicates the involvement of non-P-gp efflux transporter in digoxin secretion and this transporter is DIDS and MK571-sensitive. Contrary to conventional concept, our studies show that intestinal absorption of digoxin may involve both active uptake and efflux transporters. Our study may have clinical implications in drug-drug or drug-food interactions involving transporters.

Authors+Show Affiliations

Department of Biopharmaceutical Sciences (M/C 865), College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Chicago, IL 60612, USA. hyao@impaxlabs.comNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16781832

Citation

Yao, Hsuan-Ming, and Win L. Chiou. "The Complexity of Intestinal Absorption and Exsorption of Digoxin in Rats." International Journal of Pharmaceutics, vol. 322, no. 1-2, 2006, pp. 79-86.
Yao HM, Chiou WL. The complexity of intestinal absorption and exsorption of digoxin in rats. Int J Pharm. 2006;322(1-2):79-86.
Yao, H. M., & Chiou, W. L. (2006). The complexity of intestinal absorption and exsorption of digoxin in rats. International Journal of Pharmaceutics, 322(1-2), 79-86.
Yao HM, Chiou WL. The Complexity of Intestinal Absorption and Exsorption of Digoxin in Rats. Int J Pharm. 2006 Sep 28;322(1-2):79-86. PubMed PMID: 16781832.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The complexity of intestinal absorption and exsorption of digoxin in rats. AU - Yao,Hsuan-Ming, AU - Chiou,Win L, Y1 - 2006/05/22/ PY - 2006/01/31/received PY - 2006/05/15/revised PY - 2006/05/16/accepted PY - 2006/6/20/pubmed PY - 2006/12/9/medline PY - 2006/6/20/entrez SP - 79 EP - 86 JF - International journal of pharmaceutics JO - Int J Pharm VL - 322 IS - 1-2 N2 - The potential multiple carrier-mediated mechanisms involved in the transport of digoxin in rat intestine were investigated by the rapid filtration method in rat intestinal brush-border vesicles (BBMV) and in vitro Ussing chambers. The uptake of digoxin showed a typical overshoot phenomenon in the presence of an inward proton gradient and an outward bicarbonate gradient, or an outward glutathione gradient in BBMV. Good fitting to an equation consisting of both saturable and linear terms was obtained using non-linear regression analysis. GF120918, a specific P-gp inhibitor, significantly increased the absorptive permeability of digoxin in rat ileum (7.02 x 10(-7) cm/s versus 2.11 x 10(-6) cm/s with GF120918) but the addition of DIDS (0.5 mM), an anionic transporter inhibitor, or bromosulfophthalein (0.1 mM), an Oatp inhibitor, in the presence of GF120918 decreased the absorptive permeability compared with GF120918 alone (2.11 x 10(-6) cm/s versus 1.46 x 10(-6) cm/s, p<0.01 and 2.11 x 10(-6) cm/s versus 1.60 x 10(-6) cm/s, p<0.05, respectively). The above results suggest the involvement of carrier-mediated uptake mechanism, possibly Oatp, in digoxin absorption. Interestingly, GF120918 (1 microM) did not abolish the polarized transport of digoxin in rat jejunum and ileum, and DIDS (0.5 mM), not a P-gp inhibitor, and MK571 (50 microM), an MRP-selective inhibitor, can also significantly decrease the exsorptive permeability of digoxin. This result indicates the involvement of non-P-gp efflux transporter in digoxin secretion and this transporter is DIDS and MK571-sensitive. Contrary to conventional concept, our studies show that intestinal absorption of digoxin may involve both active uptake and efflux transporters. Our study may have clinical implications in drug-drug or drug-food interactions involving transporters. SN - 0378-5173 UR - https://www.unboundmedicine.com/medline/citation/16781832/The_complexity_of_intestinal_absorption_and_exsorption_of_digoxin_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(06)00416-9 DB - PRIME DP - Unbound Medicine ER -