Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers

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Abstract
Summary— 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 heathly 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.