Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers.
Plasma levels and urinary excretion of lormetazepam (Noctamid-ampoules; 2 mg/10 ml) were studied after i.v. (0.015 mg/kg b.w.) and after p.o (0.03 mg/kg b.w.) administration of the drug to five patients with cirrhosis of the liver (C) and to five young male volunteers (N). The cirrhotic patients exhibited higher drug plasma levels (Cmax p.o.: 11-43 ng/ml [C] vs. 11-16 ng/ml [N]) and higher AUC0-24 values of the unchanged drug (i.v.: 66-102 ng.h/ml [C] vs. 54-72 ng.h/ml [N]; p.o.: 83-188 ng.h/ml [C] vs. 74-113 ng.h/ml [N]). The absolute bioavailability was increased in the C-group with 57-134% vs. 52-84% [N]. The total plasma clearance of lormetazepam was 3 ml/min/kg in the C-group and 4 ml/min/kg in the N-group and thus within the range known for elderly and young male subjects. Conversely to the parent compound, the AUC-figures of its 3-OH-glucuronide were higher in the N-group (346-434 ng.h/ml) than in the C-group (149-371 ng.h/ml). In 24 h pooled urine samples of both groups, the glucuronide of lorazepam, the N-demethylated metabolite, accounted for approximately 5-14% of the dose fraction excreted as lormetazepam glucuronide. Apart from increased levels of the unchanged drug due to porto-systemic shunt and/or disease-dependent lower glucuronidation rate, the pharmacokinetics of lormetazepam were not altered in cirrhotic patients. It can therefore be concluded that for this group of patients the drug can be administered according to the same dose regimen as that used for normal subjects.
Hildebrand
M
M
Department of Pharmacokinetics, Schering AG, Berlin, FRG.
Hellstern
A
A
Hümpel
M
M
Hellenbrecht
D
D
Saller
R
R
D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001569:Benzodiazepines; D001682:Biological Availability; D005260:Female; D005965:Glucuronates / Q000652:urine; D006801:Humans; D007275:Injections, Intravenous; D008103:Liver Cirrhosis / Q000378:metabolism*; D008140:Lorazepam / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay; D012016:Reference Values
D014151:Anti-Anxiety Agents; D005965:Glucuronates; D001569:Benzodiazepines; C023842:lormetazepam; D008140:Lorazepam