Induction of rat intestinal P-glycoprotein by spironolactone and its effect on absorption of orally administered digoxin.
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 micromol/kg b.wt. of SL intraperitoneally for 3 consecutive days. The small intestine was divided into four equal segments of approximately 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.
Ghanem
Carolina I
CI
Departamento de Ciencias Biológicas, Universidad de Buenos Aires, Argentina.
Gómez
Paula C
PC
Arana
María C
MC
Perassolo
María
M
Delli Carpini
Griselda
G
Luquita
Marcelo G
MG
Veggi
Luis M
LM
Catania
Viviana A
VA
Bengochea
Laura A
LA
Mottino
Aldo D
AD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013148:Spironolactone; D004077:Digoxin