PHARMACOKINETICS OF MOLSIDOMINE AND ITS ACTIVE METABOLITE, LINSIDOMINE, IN PATIENTS WITH LIVER-CIRRHOSIS

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P < 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P < 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUC(linsidomine)/AUC(molsidomine) X 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P < 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.