The metabolism and pharmacokinetics of BZP and TFMPP – ‘party pill’ drugs

Abstract

Benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) are recreational drugs and the major constituents of a number of 'party pills'. Previous studies of these drugs have indicated that they may be metabolised by hepatic enzymes of the cytochrome P450 (CYP) family. However, the metabolism, pharmacokinetic properties and drug interactions of these drugs are poorly understood. This thesis aimed to develop and apply an analytical method to the detection of these drugs, to investigate their in vitro and in vivo biotransformation, to describe their pharmacokinetic properties in humans and describe the potential for drug-drug interactions. An analytical method consisting of a reversed phase HPLC system coupled with MS using an Agilent Zorbax CI8 HPLC column (4.6 x 150 mm, 5 μm) with guard column (C18, 4.6 x 10 mm, 5 μm) at 20 °C and a mobile phase of ammonium formate buffer (pH 4.5, 0.01 M, solvent A) and acetonitrile (solvent B) with a phase gradient and total run time of 15 minutes was developed and validated for the detection of BZP and TFMPP plus three hydroxylated metabolites in plasma. In vitro inhibition assays with human liver preparations were used to study the metabolism of these drugs. By using inhibitors quinidine, furafylline and troleandomycin it was found that CYP2D6, CYP1A2 and CYP3A4 metabolise both BZP and TFMPP. CYP2D6 poor metaboliser status was shown to compromise metabolism of TFMPP both in vitro and in vivo. For the human pharmacokinetic study, three groups of seven healthy human participants were dosed with either BZP HCI (200 mg) or TFMPP HCl (60 mg) or both drugs (100 mg ofBZP HCl and 30 mg ofTFMPP HCl). BZP and TFMPP reached maximum plasma concentrations of 262 ng/mL and 24.1 ng/mL at 75 minutes and 90 minutes respectively, and were cleared from the plasma of participants within 24 hr. In vitro and in vivo interactions were evident in this data, most notably the in vivo inhibition of the hydroxylation of each drug in the presence of the other. In summary, this thesis presents the results of some of the first studies on the metabolism and pharmacokinetics of these drugs in humans and sets the stage for future studies on the pharmacology of these commonly-used recreational drugs.