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The pharmacokinetic effect of a single oral in dose of 20 mg clobazam was studied in 15 patients with liver disease and in 6 healthy volunteers. Plasma concentrations of clobazam and its main metabolite, norclobazam, were measured by gas liquid chromatography. Clobazam was rapidly absorbed. Peak plasma concentrations were 350 +/- 63 ng/ml at 1.7 +/- 0.8 hr in healthy volunteers, 239 +/- 70 ng/ml at 3 +/- 1.9 hr in patients with viral hepatitis and 240 +/- 113 ng/ml at 2.5 +/- 1.5 hr in patients with cirrhosis. Total distribution volume was 173 +/- 88 l and 168 +/- 71 l in patients with viral hepatitis and cirrhosis respectively, and 81 +/- 20 l in volunteers. Corresponding half-life values were 47 +/- 18 hr and 51 +/- 21 hr in patients and 22 +/- 6.3 hr in volunteers. The difference between patients was not significant, whereas the difference between patients and volunteers was significant.

The protein C system is essential in limiting the activation ofcoagulation in vivo. We report on a 29 year old woman with Budd-Chiari syndrome and occlusion of the inferior vena cava who presented with acute liver failure. She was successfully treated with an emergency mesoatrial shunt. Eight months after surgery, she has no ascites and normal liver function. She had a low concentration of plasma protein C on admission to hospital and during the follow up. Protein C deficiency subsequently was found in her father and two sisters, who were asymptomatic. Hereditary protein C deficiency should be considered in patients with Budd-Chiari syndrome.

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.

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