Designer benzodiazepine rat pharmacokinetics: A comparison of alprazolam, flualprazolam and flubromazolam

Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and flubromazolam are structurally similar to alprazolam, they do not have an approved medical indication. Flualprazolam differs from alprazolam by the addition of a single fluorine atom. Whereas, flubromazolam differs by the addition of a single fluorine atom and substitution of a bromine for a chlorine atom. The pharmacokinetics of these designer compounds have not been extensively evaluated. In the present study, we evaluated flualprazolam and flubromazolam in a rat model and compared the pharmacokinetics of both compounds to alprazolam. Twelve male, Sprague-Dawley rats were given a 2 mg/kg subcutaneous dose of alprazolam, flualprazolam and flubromazolam and plasma pharmacokinetic parameters were evaluated. Both compounds displayed significant two-fold increases in volume of distribution and clearance. Additionally, flualprazolam displayed a significant increase in half-life leading to a nearly double half-life when compared to alprazolam. The findings of this study demonstrate that fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters including half-life and volume of distribution. The increase in these parameters for flualprazolam and flubromazolam leads to an overall increased exposure in the body and a potential for greater toxicity than alprazolam.

Automated summary

Designer benzodiazepines such as flualprazolam and flubromazolam are produced illegally to evade federal regulations. These compounds have similar structures to alprazolam but lack approved medical uses. Pharmacokinetic evaluation in rats showed that both flualprazolam and flubromazolam had significantly increased volume of distribution and clearance, with flualprazolam also demonstrating a doubled half-life compared to alprazolam. The study suggests that the fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters and potentially leads to greater toxicity.