MECHANISM OF ASCORBIC-ACID ENHANCEMENT OF THE BIOAVAILABILITY AND DIURETIC EFFECT OF FUROSEMIDE

The following possible explanations for the significant increases in t he oral bioavailability and the diuretic and natriuretic effects of or ally administered furosemide observed when ascorbic acid was coadminis tered to dogs were investigated: ascorbic acid might enhance the gastr ointestinal (GI) absorption of furosemide, might inhibit GI wall metab olism of furosemide, might enhance the reabsorption of furosemide from the renal tubules, and might increase the unionized fraction of furos emide at the receptor sites. The significant increase in the oral bioa vailability with coadministration of ascorbic acid seemed to result fr om reduced gastric first-pass metabolism of furosemide and not enhance d GI absorption of furosemide, This might be supported by rat studies; the percentages of the oral doses of furosemide recovered from the GI tract at 8 hr after oral administration were similar (p < 0.583) with out (39.5%) and with (44.7%) coadministration of ascorbic acid, and th e amounts of furosemide remaining per gram of stomach after 30-min inc ubations of 50 mu g of furosemide with 9000g supernatant fractions of stomach homogenates were increased significantly (48.5 vs. 42.4 mu g) by the addition of 100 mu g of ascorbic acid, The significant increase s in the diuretic and natriuretic effects of furosemide with ascorbic acid could be the result of increases in the reabsorption of furosemid e from renal tubules and increases in the unionized fraction of furose mide at the renal tubular receptor sites. This was supported by 1.5-4. 2-fold increases in urine output and approximately 20% decreases in th e time-averaged renal clearance of furosemide when the urine pH was de creased by 1.5-2.5 units by oral administration of ammonium chloride.