Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers.
The pharmacokinetic behaviour of flunitrazepam and its main active metabolite, N-desmethyl flunitrazepam, was investigated in 12 patients with liver disease (cirrhosis or hepatitis) compared to 6 healthy volunteers. A gas-liquid chromatographic method allowing for simultaneous determination of flunitrazepam and N-desmethyl flunitrazepam in plasma samples was developed. The accuracy and the precision near the quantification limit of ca. 1 ng/ml were better than 5%. Plasma levels of flunitrazepam were not significantly altered by hepatic failure, whereas plasma levels of N-desmethyl flunitrazepam were lower in patients than in healthy subjects. Pharmacokinetic parameters did not differ significantly between healthy subjects and liver disease patients: the oral clearance was 3.5 +/- 0.8, 3.5 +/- 1.9 and 4.0 +/- 1.2 ml/min/kg, respectively in healthy subjects, patients with hepatitis and patients with cirrhosis. The apparent elimination half-life was 22 +/- 5 h in healthy subjects, 25 +/- 10 h in patients with hepatitis and 20 +/- 6 h in patients with cirrhosis. However, the expected increase of the drug free fraction during liver disease could decrease the therapeutic and toxic ranges of flunitrazepam in these patients.
Drouet-Coassolo
C
C
INSERM U 278, Faculté de Pharmacie, Marseille, France.
Iliadis
A
A
Coassolo
P
P
Antoni
M
M
Cano
J P
JP
D000284:Administration, Oral; D000328:Adult; D002849:Chromatography, Gas; D005445:Flunitrazepam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006525:Hepatitis, Viral, Human / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged
C069164:N-desmethylflunitrazepam; D005445:Flunitrazepam