Human and Animal Study on Elimination from Plasma and Metabolism of Diazepam after Chronic Alcohol Intake

Abstract

Very significantly lower concentrations of diazepam at 15 minutes and 1 hour after 10 mg intravenous diazepam injection were found in chronic alcoholic patients in comparison to healthy controls. Compared to 13 healthy controls a more rapid elimination of diazepam from the plasma of 14 chronic alcoholic patients during their alcohol-free period was observed. The alcoholics had a smaller concentration of the diazepam main metabolite, N-demethyldiazepam, and at 3 hours this difference was significant. The concentrations of free plasma oxazepam as a metabolite of diazepam, were not observed after a single dose of diazepam either in the alcoholics or in volunteers. A more rapid elimination of diazepam after 5 mg/kg intraperitoneally in the plasma of rats pretreated with ethyl alcohol (15 % in drinking water for 3 weeks) was found than in the control rats. Pretreatment of rats with ethyl alcohol increased significantly the concentration of the hydroxylated metabolite, free oxazepam, in the plasma, but not of the demethylated metabolite, N-demethyldiazepam.

Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry

“…It also agrees with the results of our studies of CYP2E1-CYP3A4 interactions with LRET [32] and homo-FRET [25] techniques. Extensive interactions of CYP2E1 with CYP3A4 suggested by our results provide possible explanations for the alcoholinduced increase in the metabolism of diazepam and doxycycline [17][18][19], the substrates of CYP3A enzymes. Furthermore, CYP2E1 interactions with CYP2A6 suggested by our results may give a clue for the increased rate of metabolism of nicotine, a CYP2A6 substrate, in alcohol-dependent smokers [33].…”

“…However, the impacts of the alcohol-induced increase in CYP2E1 content in the human liver on drug metabolism and other functions of the cytochrome P450 ensemble appear to be underestimated. The effects of interactions of CYP2E1 with other P450 enzymes provide the most likely explanation for the alcohol-induced increase in the metabolism of diazepam and doxycycline [17][18][19], the substrates of CYP3A, or phenytoin, tolbutamide, and warfarin [20][21] metabolized primarily by CYP2C9. Conclusive evidence of a direct cause-to-effect relationship between alcohol-dependent induction of CYP2E1 and the effects of this kind is provided by our studies of the impact of CYP2E1 on the activity of CYP3A4, CYP1A2, and CYP2C19 in HLM [22][23].…”

Enzyme Inducing Effects of Phenobarbital on Nitrazepam Metabolism in Dogs

“…The intravenous injection of diazepam during the chronic diazepam treatment in psychiatric patients shows significantly lower increase of dia-zepam concentration in plasma as a sign of autoinduction, and significantly higher concentration of diazepam metabolite, N-demethyldiazepam, than without simultaneous continuous diazepam therapy (Sellman et a/. 1975a).…”

Exploring the Interactome of Cytochrome P450 2E1 in Human Liver Microsomes with Chemical Crosslinking Mass Spectrometry

“…However, the impacts of the alcohol-induced increase in CYP2E1 content on drug metabolism and other functions of the P450s appear to be underestimated. The effects of interactions of CYP2E1 with other P450s provide the most likely explanation for the alcohol-induced increase in the metabolism of diazepam and doxycycline [ 17 , 18 , 19 ], the substrates of CYP3A, or phenytoin, tolbutamide, and warfarin [ 20 , 21 ] metabolized primarily by CYP2C9. Conclusive evidence of a direct cause-to-effect relationship between alcohol-dependent induction of CYP2E1 and the effects of this kind is provided by our studies of the impact of CYP2E1 on the activity of CYP3A4, CYP1A2, and CYP2C19 [ 22 , 23 ].…”