Flunitrazepam alters the toxicokinetics of chlorpromazine enhancing its toxicity

Abstract

Flunitrazepam, a highly potent benzodiazepines, has a wide safety margin and widely used for insomnia treatment. However, a number of fatal poisoning cases involving a combination of flunitrazepam and other drugs have been reported. In instances of drug overdose deaths involving flunitrazepam in Japan, antipsychotic drugs like chlorpromazine are frequently used concomitantly. This study seeks to elucidate the pharmacokinetic interactions during the overdose of concurrent drugs, with a specific focus on the toxic effects of elevated doses of flunitrazepam and chlorpromazine in mice. Male ICR mice were intraperitoneally administered chlorpromazine (90 mg/kg) and flunitrazepam (200 mg/kg) either alone or concurrently. Body temperature was measured up to 24 hr after administration, and the number of deaths within 24 hr was quantified for each group. Additionally, flunitrazepam, chlorpromazine, and its active metabolite 7-hydroxychlorpromazine concentrations in serum and brain extracellular fluid were measured up to 24 hr after administration. Flunitrazepam enhanced the hypothermic effect of chlorpromazine, and acute intoxication deaths occurred only in the combination group. Cmax and AUC_0-24h of flunitrazepam in serum and brain were not affected by concomitant administration with chlorpromazine. While flunitrazepam significantly increased the AUC_0-24h of chlorpromazine, and the Cmax and AUC_0-24h of 7- hydroxychlorpromazine in serum. Flunitrazepam was shown to alter the toxicokinetics of chlorpromazine when administered in combination, thereby augmenting the toxicity of chlorpromazine and leading to lethal drug intoxication. This study underscores the significance of comprehending toxicokinetics not only for individual agents but also when utilized in combination.