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

Abstract

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 mol/kg b.wt. of SL intraperitoneally for 3 consecutive days. The small intestine was divided into four equal segments of ϳ25 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.

Effects of borneol on the intestinal transport and absorption of two P-glycoprotein substrates in rats

“…The efflux ratio of absorptive transport (M to S) was increased significantly, while the secretory transport (S to M) decreased, compared to the control. Previous studies indicated that the secretory-directed transport of other P-gp substrates, like methyprednisolone and prednisolone could be inhibited in the presence of other P-gp inhibitors, such as verapamil, diltiazem and digoxin, in rats (Molden et al, 2000;Ghanem et al, 2006;Hsiao et al, 2006). Moreover, our previous study also demonstrated that PEG 20000 reduced the efflux ratio of rhodamine123 in the intestine (Shen et al, 2008).…”

Regulation of hepatic bile acid transporters Ntcp and Bsep expression

“…Therefore, mechanisms other than PXR are involved in Bsep induction by spironolactone. For example, Ghanem et al [59] showed that in rats, spironolactone treatment increased p-glycoprotein expression and thus decreased intestinal absorption and liver content of digoxin. Therefore, spironolactone may be capable of altering disposition of some exogenous or endogenous compounds, such as bile acids, which might be responsible for regulation of Bsep.…”

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis

“…The ocular biodisponibility of spironolactone and eplerenone after systemic administration has not been studied but spironolactone induces the expression of the P-glycoprotein, a drug efflux protein that regulates the bloodebrain barrier, and is one of its ligands (Ghanem et al, 2006).…”