QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.105668v1 318/3/1146    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ghanem, C. I. Articles by Mottino, A. D. Search for Related Content PubMed PubMed Citation Articles by Ghanem, C. I. Articles by Mottino, A. D.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Induction of Rat Intestinal P-glycoprotein by Spironolactone and Its Effect on Absorption of Orally Administered Digoxin

Cátedra de Fisiopatología, Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina (C.I.G., P.C.G., M.C.A., M.P., G.D.C., L.A.B.); and Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina (M.G.L., L.M.V., V.A.C., A.D.M.)

The effect of the diuretic spironolactone (SL) on expression and function of intestinal P-glycoprotein (P-gp), as well as its impact on intestinal absorption of digoxin, was explored. Rats were treated with daily doses of 200 µmol/kg b.wt. of SL intraperitoneally for 3 consecutive days. The small intestine was divided into four equal segments of 25 cm, with segment I being the most proximal. Brush-border membranes were isolated and used in analysis of P-gp expression by Western blot analysis. P-gp content increased in the SL group by 526, 292, 210, and 622% over controls for segments I, II, III, and IV, respectively. Up-regulation of apical P-gp was confirmed by immunofluorescence microscopy. P-gp transport activity was explored in intestinal sacs prepared from segment IV using two different model substrates. Serosal to mucosal transport (efflux) of rhodamine 123 was 140% higher, and mucosal to serosal transport (absorption) of digoxin was 40% lower in the SL group, both indicating increased P-gp function. In vivo experiments showed that intestinal absorption of a single dose of digoxin administered p.o. was attenuated by SL pretreatment. Thus, concentration of digoxin in portal and peripheral blood was lower in SL versus control groups, as well as its accumulation in kidney and liver. Urinary excretion of digoxin was significantly decreased in the SL group, probably reflecting decreased systemic availability of digoxin for subsequent urinary elimination. We conclude that SL induces P-gp expression with potential impact on intestinal absorption of substrates with therapeutic application.

Address correspondence to: Dr. Aldo D. Mottino, Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipacha 570, (S2002LRL)-Rosario, Argentina. E-mail: amottino{at}unr.edu.ar

This article has been cited by other articles:

				J. M. A. Delou, A. G. Lopes, and M. A.M. Capella Unveiling the Role of Multidrug Resistance Proteins in Hypertension Hypertension, August 1, 2009; 54(2): 210 - 216. [Full Text] [PDF]

				A. Arias, S. S. M. Villanueva, M. L. Ruiz, M. G. Luquita, L. M. Veggi, J. M. Pellegrino, M. Vore, V. A. Catania, and A. D. Mottino Regulation of Expression and Activity of Rat Intestinal Multidrug Resistance-Associated Protein 2 by Cholestatic Estrogens Drug Metab. Dispos., June 1, 2009; 37(6): 1277 - 1285. [Abstract] [Full Text] [PDF]