Role of binding in distribution of furosemide: where is nonrenal clearance?

Furosemide is an acidic drug that binds tightly to anionic binding sites on albumin, but has negligible binding to tissue proteins. As a consequence, it has a low volume of distribution of total drug at steady state (Vdss total), which is less than extracellular fluid volume. With decreases in serum albumin concentration, plasma protein binding decreases, total Vdss increases, and Vdss of free drug decreases in a manner that is quantitatively consistent with no change in tissue binding. The elimination of furosemide is partly by renal clearance of unchanged drug (predominantly because of renal tubule secretion) and partly by nonrenal routes. Glucuronidation appears to occur in extrahepatic sites in dogs and, possibly, humans. Residual nonrenal elimination is not influenced by liver disease but is reduced by probenecid pretreatment and uremia. Furthermore, there is appreciable recovery of 35S-labeled furosemide in feces after i.v. administration without the appearance of 35S in the bile. These observations are consistent with the hypothesis of active secretion of furosemide into the gut. The independent variables of distribution and elimination contribute to determine intersubject variability of plasma concentration-time profiles in health and disease and, therefore, are important in determining the extent and duration of diuretic response.