Evaluation of potential causes for the incomplete bioavailability of furosemide: Gastric first-pass metabolism

Abstract

Potential causes for reported incomplete (usually 40-60%) and often highly variable (e.g., 11-79%) bioavailability of furosemide in humans were investigated. The drug was found to be fairly stable in gastric fluids and its hepatic first-pass elimination (HFPE) was estimated to be much less than 6% based on published i.v. data. The rat was used as the main model for extensive evaluation. About 4% (n = 4) of dose was recovered unchanged in the GI tract after i.v. injection while about 40% (n = 12) was recovered after a 120-fold (0.05-6 mg) dose range of oral administration. In another study 70% of the oral dose eventually disappearing (presumably due to absorption and first-pass elimination) from the GI tract was estimated to occur in just 20 min. These data indicate an unsaturable, incomplete, site-specific absorption as well as a lack of dissolution-rate-limited absorption at the doses studied. Based on plasma data, oral bioavailability in four rats was only 30%, and the HFPE much less than 10%. After oral administration, 61% of the dose was absorbed and/or metabolized in the GI recovery study. Thus, 20-30% of oral dose in rats must be metabolized in the GI wall during absorption. The metabolic activity of stomach (homogenate) from 5 rats was found to be much (e.g., 5-10.5-fold) greater than those of liver and small intestine. This was also confirmed in preliminary studies with 3 rabbits and 1 dog. Large intersubject variability in enzyme activity was found in rats and rabbits. The phenomenon of a presystemic first-pass effect was also substantiated by urinary excretion data of a metabolite. It is postulated that variable gastric and intestinal first-pass metabolism may be a major factor causing incomplete and irregular absorption of furosemide in humans.

Effects of Acute Renal Failure on the Pharmacokinetics of Chlorzoxazone in Rats

“…administration of CZX were unconjugated CZX (not CZX glucuronides) and conjugated OH-CZX, respectively. The percentage of hepatic extraction ratio (hepatic firstpass effect) was roughly estimated by dividing the nonrenal clearance (as mentioned earlier, the CL of CZX in Table 3 could represent the metabolic clearance of CZX) by the reported hepatic plasma flow in rats assuming that nonrenal clearance of CZX was attributed solely to the liver (hence the percentage represents maximal possible value) (Lee and Chiou, 1983). The hepatic plasma flow in rats was estimated based on the reported hepatic blood flow of 30.4 ml/ min/kg (Davies and Morris, 1993) and hematocrit of approximately 45% (Mitruka and Rawnsley, 1981) in rats.…”

Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus

“…The pharmacokinetics and/or pharmacodynamics of furosemide, a loop diuretic, in humans [6][7][8] and animals [9][10][11][12][13][14] have been extensively studied, however, the effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of furosemide seemed not to be thoroughly studied. Pharmacokinetic and pharmacodynamic changes of azosemide, another loop diuretic, after its intravenous (i.v.)…”

Time-Dependent Effects of Klebsiella Pneumoniae Endotoxin (KPLPS) on the Pharmacokinetics of Theophylline in Rats: Return of the Parameters in 96-Hour KPLPS Rats to the Control Levels

“…Thus, it could be expected that, compared with control rats, the CL NR of theophylline would be slower in 24-h KPLPS rats, because theophylline is a low hepatic extraction ratio drug in rats. The hepatic first-pass effect of theophylline in this study was estimated using a reported equation (Lee and Chiou, 1983) based on the CL NR of …”