Mechanism of enhanced bioavailability and diuretic effect of azosemide by ascorbic acid in rats.
To increase the extent of comparative oral bioavailability (F) value and the diuretic and natriuretic effects of orally administered azosemide, ascorbic acid was coadministered to rats. The rationales for this study are that ascorbic acid might inhibit intestinal first-pass effect of azosemide and might increase the unionized fraction of azosemide at the receptor sites. After oral administration of azosemide (20 mg/kg) with 100 mg of ascorbic acid, the F value (138% vs. 100%), 8-h urinary excretion of azosemide (5.18% vs. 1.32% of oral dose), 8-h urine output (41.3 vs. 23.0 ml), and 8-h urinary excretion of sodium (24.6 vs. 15.3 mmol/kg) were greater than controls (without ascorbic acid). The amount of spiked azosemide remaining after 30 min incubation of 50 mug of azosemide with the 9000 g supernatant fraction of rat small intestine was significantly greater by 100 microg of ascorbic acid (45.3 vs. 40.9 microg) than controls (without ascorbic acid). After oral administration of azosemide with NH4Cl, the urine pH decreased by 0.5 U, and 8-h urine output (25.8 vs. 11.0 ml) and 8-h urinary excretion of sodium (13.3 vs. 6.89 mmol/kg) were significantly greater than controls (without NH4Cl). The increase in F value and diuretic and natriuretic effects of azosemide with coadministration of ascorbic acid seemed to be due to reduced intestinal first-pass metabolism of azosemide, increased urinary excretion of azosemide, and increased unionized fraction of azosemide at the renal tubular receptor sites.
Choi
Ka Y
KY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Kwanak-Gu, Seoul 151-742, South Korea.
Kim
Yu C
YC
Lee
Myung G
MG
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001682:Biological Availability; D004232:Diuretics / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D017693:Sodium Bicarbonate / Q000494:pharmacology; D013424:Sulfanilamides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014018:Tissue Distribution; D014556:Urine / Q000737:chemistry; D014815:Vitamins / Q000494:pharmacology*; D013777:Tetrazoles; D013876:Thiophenes; D000096926:Benzenesulfonamides
D000643:Ammonium Chloride; D000975:Antioxidants; D001205:Ascorbic Acid; D004232:Diuretics; D012964:Sodium; D017693:Sodium Bicarbonate; D013424:Sulfanilamides; D014815:Vitamins; C018222:azosemide; D013777:Tetrazoles; D013876:Thiophenes; D000096926:Benzenesulfonamides