A Preliminary Study On The Median Lethal Dose And Pharmacokinetic Of Diazepam Affected By Ethanol

【Backgroud and Objective】Combined poisoning cases often occur in forensic practice.In some cases, the single toxic dose is less than the lethal dose, but due to the synergeticaction between the toxins, death can occur. Diazepam (Valium), a benzodiazepam drug, hasbeen used for its sedative and hypnotic effect worldwide. A variety of alcoholic beveragesexists worldwide, and that increases the risk of diazepam and ethanol being combined andcause poisoning in an accident，in suicides，or in homicide cases. Both diazepam andethanol has inhibitory effects on the central nervous system. Co-administration can lead totoxicity and cause acute poisoning or death. But there is no clear demarcation concerningthe difference between their lethal dose and the fatal blood concentration especially whencombined and when used alone. This results in disputes on the lethal dose of diazepam andethanol, and causes controversy and difficulty in forensic investigation.Therefore，this study observed the changes on lethal dose and pharmacokinetics ofdiazepam used alone and combined with different doses of ethanol. This is helpful to solvethe controversy and the above shortcomings. and also experimental data for forensictoxicology investigation is being reinforced.【Material and Methods】1. In this part，female mice were used in the acute oral toxicityexperimental AOT425program, to determine the median lethal dose（LD50value） ofdiazepam when used alone and combined with different doses(low, medium and high dose)of ethanol.2. Female mice were exposed to different doses of DZ（50mg/kg、100mg/kg、200mg/kg）alone and combined with different doses of ethanol（1150mg/kg、1725mg/kg、2300mg/kg）respectively. HPLC was implied to detect the concentration of DZ and its main metabolites, nordiazepam(NDZ) and oxazepam(OXZ), in heart blood at early stage（s15min,30min and60min）.【Results】1. The LD50value of diazepam was lower in DZ+EtOH groups. The decreaseof LD50value was positively correlated with the increase of EtOH dosage.2. In theDZ+EtOH groups，the concentrations of DZ and OXZ were lower than DZ groups in theearly stage, in50mg/kg,100mg/kg DZ+EtOH groups，the concentration of NDZ wassignificantly higher at60min than50mg/kg,100mg/kg DZ groups, but the effect of EtOHdosage was not obvious; in200mg/kg DZ+EtOH (low, medium dose) groups, theconcentration of NDZ was lower than the200mg/kg DZ group at60min.【Conclusions】1. There was toxicity synergy(interaction) between diazepam and ethanol.The LD50value of diazepam changes with EtOH dosage in combined poisoning.2.At anearly stage, the concentration of diazepam and oxazepam were decreased when combinedwith ethanol, and ethanol can inhibit the metabolism of nordiazepam, and increase theconcentration of nordiazepam. Nordiazepam was meaningful in the early stage of toxicitysynergy (toxic interaction) between diazepam and ethanol.