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

Abstract

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.

Concentrations of Scheduled Prescription Drugs in Blood of Impaired Drivers: Considerations for Interpreting the Results

“…[61][62][63][64] Liver and kidney function deteriorates with advancing age and this is considered when a physician prescribes medication to the elderly. 65,66 People in need of palliative care receiving longterm treatment with strong analgesics can seemingly tolerate unusually high concentrations of, eg, opiates, well above normal therapeutic concentrations and do not necessarily represent a danger for traffic safety. 67 Opiates are a diverse group of pharmaceutical agents with high abuse potential and toxicity after taking an overdose.…”

The advantage of dual‐column approach and retention indices combined with refined reporting in gas chromatographic drug screening

“…Gas chromatography-mass spectrometry (GC-MS) has found an established position in the screening and confirmation analysis of drugs in urine samples [26]. However, drug concentrations in the blood are usually too low for screening quantitatively small volume samples by GC-MS, and consequently only individual drugs or certain groups of drugs, such as benzodiazepines [27], have been screened using the selected ion monitoring mode. Since a great majority of drugs contains nitrogen, the use of GC with nitrogen/phosphorus detection offers a facile, selective and sensitive means for quantitative screening.…”

Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam

“…Whereas the disposition of the relatively more polar benzodiazepines, such as the hydroxylated compounds, which are excreted as glucuronated metabolites, is unchanged in liver disease [5][6][7][8], the lipid-soluble drugs which are excreted as oxidised metabolites have longer half-lives in patients with this disease, with reduced total drug clearance and, for some drugs, also a larger volume of distribution [9][10][11][12][13][14][15][16][17][18]. The unbound fraction of the drugs which have been studied is also higher in patients with liver disease, therefore, the unbound clearance is also reduced [15] and volume of distribution increased [3,15].…”