Altered kinetics of etozolin and its active metabolite ozolinone in hepatitis and hepatic cirrhosis with ascites.
The single dose kinetics of (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin) and its active metabolite ozolinone were determined in 6 healthy volunteers, in 12 patients with acute hepatitis and in 15 patients with hepatic cirrhosis with ascites. In hepatitis, the elimination half-life of etozolin was 4 times longer resulting in a 2 fold rise in the AUC. At the same time, plasma levels of ozolinone were lower and consequently the AUC of his metabolite was reduced. In cirrhosis, the plasma level time curves of etozolin and ozolinone differed significantly from the controls and also from those of the patients with acute hepatitis. For etozolin Cmax was reduced to about 1/2, the elimination half-life being increased by a factor of 5. This resulted in a 3 fold higher AUC. As for ozolinone the reduction of plasma levels was more pronounced--Cmax fell to 1/6 of the control value--so that in spite of a longer elimination half-life, the AUC fell to 1/2. Ascites concentrations of etozolin and ozolinone were almost identical to the plasma concentration. The results suggest that acute hepatitis and hepatic cirrhosis lead to a reduced formation of ozolinone. As a result, etozolin accumulates and plasma levels of oxolinone drop. Moreover, both substances enter the ascites to a significant degree. It is concluded that these changes in the kinetics of this lipophilic diuretic do not allow a reliable dosage regimen in patients with hepatic cirrhosis and ascites.
Knauf
H
H
Medizinische Universitätsklinik Freiburg/Brsg., Fed. Rep. Germany.
Missmahl
M
M
Schölmerich
J
J
Gerok
W
W
Mutschler
E
E
D000208:Acute Disease; D000328:Adult; D000368:Aged; D001201:Ascites / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D001202:Ascitic Fluid / Q000032:analysis; D004232:Diuretics / Q000493:pharmacokinetics*; D006207:Half-Life; D006525:Hepatitis, Viral, Human / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000493:pharmacokinetics*
D004232:Diuretics; D013844:Thiazoles; C018121:ozolinone; C015208:etozolin