The evaluation of the diuretic action of parenteral formulations of metolazone

BACKGROUND AND OBJECTIVES: This study was design to compare the diuretic and natriuretic effects of the 2 parenteral formulations of metolazone and the combination of these 2 formulations of metolazone with the parenteral administration of furosemide. Metolazone is an anthracrene acid derivate and manifests a dual diuretic effect on the proximal and distal tubule with a minimal kaluretic effect. It is currently only marketed in an orally administrable formulation, and this has limited its utility in critically ill patients. Metolazone given orally and furosemide given orally or parenterally are frequently administrated together when furosemide alone is clinically inadequate at producing a desired diuresis. METHODS: Sprague Dawley male rats (400 to 450 g) were divided into groups to receive a parenteral formulation of metolazone or furosemide administrated separately intraperitoneally (IP) or administrated IP in combination with one another. Tris buffer-administered IP was used as a control vehicle comparator. The urine volume voided over the following 24 hours was collected, measured and analyzed for sodium content. RESULTS: Vehicle (Tris buffer) caused 9 ± 1 mL/d output of urine with a sodium [Na] concentration of 194 ± 41 μmol/L (n = 6 per group). Metolazone 2 mg/kg resulted in 16 ± 3 mL/d urine output and sodium [Na] of 278 ± 76 μmol/L (n = 6 per group). Furosemide 2, 4, and 6 mg/kg resulted in a volume of urine 9 ± 1, 14 ± 2 and 17 ± 2 mL/d and [Na] μmol/L of 194 ± 41, 206 ± 108, and 229 ± 91, respectively. Metolazone 4 mg/kg combined with furosemide 4 mg/kg resulted in a urine volume of 21 ± 1 mL/d and [Na] of 326 ± 108 μmol/L. CONCLUSION: Combining metolazone and furosemide can cause an increase in urine volume and sodium excretion. Metolazone administrated parenterally in combination with the parenteral administration of furosemide appears to have an important clinical potential.