Clinical Pharmacokinetics and Pharmacodynamics of Torasemide

Abstract

The new loop diuretic torasemide belongs to the pyridine sulfonylurea class. It is well absorbed and yields a bioavailablity of about 80% in healthy individuals, even higher in patients with oedema. This is roughly double that of the 'classical' loop diuretic furosemide (frusemide) [26 to 65%]. Torasemide is highly bound to protein (99%) as is furosemide. The volume of distribution of torasemide was determined as 0.2 L/kg as compared with 0.11 to 0.18 L/kg for furosemide. Torasemide undergoes extensive hepatic metabolism; only 20% of the parent drug is recovered unchanged in the urine. For comparison only 10 to 20% of furosemide undergoes phase II metabolisation (to the glucuronide). In chronic renal failure the renal clearance of torasemide decreased in proportion to the decrease of the patients' glomerular filtration rate, whereas the total plasma clearance (3 times that of the renal clearance) appeared to be independent of renal function. As expected, the renal excretion of torasemide metabolites is significantly retarded in renal disease. The pharmacokinetics of torasemide are significantly influenced by liver disease. Total plasma clearance of torasemide was reduced to about half of that found in the control group, yielding an increase in elimination half-life. A greater than normal fraction of torasemide was recovered in the urine of patients with cirrhosis. In contrast, the kinetics of furosemide appeared to depend more on kidney function than on liver disease. The pharmacodynamics of torasemide are principally the same as those reported from conventional loop diuretics due to their interference with one binding site in the thick ascending limb of Henle's loop, the Na+:K+:2Cl- carrier. The maximum natriuretic effect of all loop diuretics amounts to about 3 mmol Na+/min. Members of this class differ, however, with respect to their intravenous potency or affinity for the receptor, respectively: bumetanide > piretanide > torasemide > furosemide. So far, the only loop diuretic which has been shown to effectively lower high blood pressure is torasemide. This effect occurs at the low dose of 2.5 mg/day.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Approximately 20% of torsemide is eliminated unchanged in the urine, whereas M1 and M5 comprise 10 and 50% of a torsemide dose excreted renally, respectively (Miners et al, 1995;Knauf and Mutschler, 1998). A human study showed 1.5-, 1.7 and 2.8-fold higher torsemide AUCs with the CYP2C9*1/*3, *2/*3, and *3/*3 genotypes, respectively, whereas those with the *1/*2 genotype behaved similarly to the wild type (Vormfelde et al, 2004).…”

Torasemide Transport by Organic Anion Transporters Contributes to Hyperuricemia

“…A quantification of torasemide and its metabolites in urine revealed 21 to 25% torasemide, 11% M1, 3% M3, and 34 to 44% M5, resulting in a total renal clearance of Ͼ80% for torasemide and its metabolites. 2,6 The calculated renal clearance of free torasemide (not bound to plasma protein) was approximately 640 ml/min, 3 which is equal to renal plasma flow. The high clearance for torasemide indicated the involvement of active secretory mechanisms in proximal tubule cells.…”

“…In contrast, the classical loop diuretic furosemide has a bioavailability of only 26 to 60%. 2,3 Torasemide is highly bound to plasma proteins, and its elimination half-life is almost 6 h, which is approximately three-fold higher than that of furosemide or bumetanide. Torasemide shares a similar mechanism of inhibition of Na ϩ -K ϩ -2Cl Ϫ reabsorption at the thick ascending limb of Henle's loop with furosemide or bumetanide.…”

“…The diuretic potencies of M1 and M3 are different. 3,5,6 M1 exhibits only 10% of the diuretic effect, whereas M3 possesses a similar potency as the parent drug; M5 is diuretically inactive. A quantification of torasemide and its metabolites in urine revealed 21 to 25% torasemide, 11% M1, 3% M3, and 34 to 44% M5, resulting in a total renal clearance of Ͼ80% for torasemide and its metabolites.…”

“…Simultaneous administration of torasemide and probenecid lowered the diuretic effect and reduced torasemide clearance, suggesting organic anion transporters (OAT) to be involved in renal secretion, because probenecid is the classical inhibitor of OAT. 3,4 The aim of this study was to elucidate the interaction of torasemide and its metabolites with human OAT and to understand the background of the pronounced clinical advantage of torasemide on the molecular level. Furthermore, we aimed to identify the influence of torasemide on the OAT-mediated urate transport.…”