Metabolic Interactions with Piperazine-based 'party Pill' Drugs

Objectives: 'Party pills' have found use worldwide as a substitute for amphetamine-derived designer drugs. Whilst some information exists about the metabolism of these drugs, there is little information about their ability to inhibit the metabolism of co-administered drugs. This study aimed to determine whether predictions can be made about global interactions between 'party pills' constituents and other drugs metabolised by the same cytochrome P450 (CYP) isoenzymes.

Methods: The inhibitory effects of seven benzyl and phenyl piperazines were measured in microsomal incubation assays of probe substrates for five major CYP isoenzymes. In addition, the metabolism of benzylpiperazine and trifluoromethylphenylpiperazine, the two most commonly used constituents of 'party pills', was investigated using human liver microsomes assays and known inhibitors of CYP isoenzymes.

Key Findings: All piperazine analogues tested showed significant inhibitory activity against most, if not all, isoenzymes tested. The metabolism of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) involved CYP2D6, CYP1A2 and CYP3A4. Furthermore, BZP and TFMPP inhibited each other's metabolism.

Conclusions: Fluorophenylpiperazine, methoxyphenylpiperazine, chlorophenylpiperazine, methylbenzylpiperazine and methylenedioxybenzylpiperazine had significant inhibitory effects on CYP2D6, CYP1A2, CYP3A4, CYP2C19 and CYP2C9 isoenzymes but each piperazine had a different inhibitory profile. The metabolic interaction between BZP and TFMPP may have clinical implications, as these agents are often combined in 'party pills'.