Pharmacokinetics and pharmacodynamics of azosemide

Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.     

Azosemide-Induced Fetal Wavy Ribs and Their Disappearance after Birth in Rats

ABSTRACT Azosemide produced bent long bones such as wavy ribs in rat fetuses, but these abnormalities could not be found in the adult offspring. In the present study, the morphological sequence from appearance to disappearance of wavy ribs was examined in cartilage-bone double stained specimens of fetuses and pups from mothers treated with azosemide on day 16 of gestation. The first detected change of the skeletal abnormalities was inhibition of bone deposition in the ossification centers of fetuses on day 17 of gestation. A bend first appeared on day 18 of gestation, and consisted of cartilage and portion stained neither alcian blue nor alizarin red S. Ossification began at this stage. From day 19 of gestation onward, ossification progressed toward the ends of the cartilage model including the bent region. The bend disappeared in most pups as bone in the bent region grew on days 10–14 postpartum. The present findings imply that the bend may be caused by difference in growth between cartilaginous and unstained portions, and a surface remodeling of bones may straighten the bend in the subsequent bone growth.