Acute and chronic effects of torasemide in healthy volunteers
Lameire, N.; Dodion, L.
Arzneimittel-Forschung 38(1a): 167-171
1988
ISSN/ISBN: 0004-4172 PMID: 3370064 Document Number: 311286
The acute and chronic effects of torasemide (l-isopropyl-3-{[4-(3-methyl-phenylamino)pyridine]-3-sulfonyl}urea) were investigated in 2 separate groups of healthy volunteers: In a first group of 6 volunteers, the acute effects of torasemide were investigated at 3 different steady state plasma and urinary drug levels and compared to those of furosemide according to a randomized cross-over design. Each drug was continuously given by i.v. route in 3 consecutive periods of 90 min immediately after a control run-in period of 90 min. The last 30 min period of each control and 3 drug administration periods fulfilled the steady state conditions and were used for clearance determination and plasma and urinary concentrations of drug. The plasma levels of both torasemide and furosemide increased progressively at increasing plateaus during each of the 3 drug periods with no significant difference between each of the 2 drugs. However, the urinary drug excretions were 5 times lower with torasemide than with furosemide. In spite of these highly different urinary drug concentrations, torasemide and furosemide induced a similar increased of the water excretion, osmolar and creatinine clearances and absolute and fractional excretions of sodium, potassium, chloride, calcium and magnesium. The correlation between the logarithm of the drug doses and the urinary effects were highly significant with both drugs. Free water clearance was stable throughout the torasemide administration, whereas it increased steadily with each dose of furosemide. The fractional distal chloride reabsorption decreased significantly more with each dose of furosemide. The fractional distal chloride reabsorption decreased significantly more with torasemide than with furosemide. In a second group of 8 volunteers, torasemide was given orally for 21 days to investigate its chronic effects and its clinical tolerance. The daily dose was 20 mg b.i.d. An intense water, sodium and chloride excretion was induced at the beginning of the treatment. This effect gradually faded out and the electrolyte excretion fell below control values at the end of the treatment. Plasma levels of sodium remained unaltered throughout the treatment; those of chloride and potassium were slightly but significantly decreased. Calcium and magnesium plasma levels transiently increased during the midth of the treatment. There was no change of the fasting glucose tolerance test. Alterations in lipid metabolism were either absent or minimal. Uric acid plasma levels were moderately increased. The plasma pharmacokinetics of torasemide remained unchanged after 3 weeks of therapy. In spite of the high doses used, torasemide was well tolerated as well in the acute as in the chronic study. Side effects were mainly low-back pain and fatique when an intense diuresis was induced. No adverse toxic effects were observed.