Pharmacokinetics of ‘party pill’ drug N-benzylpiperazine (BZP) in healthy human participants U. Antia a, *, H.S. Lee a , R.R. Kydd b , M.D. Tingle c , B.R. Russell a a School of Pharmacy, University of Auckland, Private Bag 92019, Auckland, New Zealand b Department of Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand c Department of Psychological Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand 1. Introduction N-Benzylpiperazine (BZP) (Fig. 1) and related active ingredients of ‘party pills’, such as trifluoromethylphenyl piperazine (TFMPP), methoxyphenyl piperazine, chlorophenyl piperazine and fluoro- phenyl piperazine, are used extensively as recreational drugs around the world despite their prohibition in several countries [1]. While most psychostimulants in use recreationally were initially used as medications with extensive testing prior to human use, there is very little available information about the mode of action, toxicity or pharmacokinetics of BZP and its analogues. Recent studies have investigated the in vitro metabo- lism of BZP and TFMPP as well as the effect of these compounds on the hepatic metabolism of other drugs [2,3]. BZP and several metabolites have been detected in urine from rats and humans [4,5]. EEG trials have also been conducted, demonstrating the effects of BZP and TFMPP on the human brain [6–8]. Early studies comparing the effects of BZP to dexamphetamine in humans suggest these two drugs have similar effects [9,10] and others have also suggested that BZP has abuse liability similar to that of the amphetamines [11]. Conspicuously missing from the available literature is information regarding the pharmacokinetics of BZP and related compounds. While previous case reports have indicated that BZP is detectable in urine following ingestion [12], no previous studies report the concentrations of this drug (in urine or other tissues) in humans. This report discusses the findings of a pharmacokinetic study of BZP in seven healthy human participants following a single oral dose. 2. Participants and methods 2.1. Study protocol Healthy human volunteers (n = 7, males, 19–31 years, mean body mass index (BMI): 24.3) took part in this study. In order to minimise risk to participants, strict exclusion criteria were used i.e. history of drug allergies, liver disease, endocrine disorder, cardiovascular disease, drug or alcohol addiction, mental illness or respiratory disease. Ethical approval to carry out this research was granted by the Northern X Regional Ethics Committee of NZ (NTX06/07/080). Participants were fasted for 12 h prior to drug administration, and were then provided with standardised meals 120 min and 400 min after drug ingestion; water was freely available during the course of the study. BZP hydrochloride (200 mg; Sigma Aldrich, New Zealand) in gelatine capsules (Size 0CS; Capsugel, USA) was given as a single oral dose and 15 blood samples were collected over a 24-h period. One blood sample was taken before drug administration (t = 0) and 14 additional samples were taken post-dose at t = 15, 30, 45, 60, 75, 90, 105, 120, 180, 240, 300, 350, 480 and 1440 min. The total volume of urine excreted over the 24 h test period was also collected for analysis. 4 0 -Hydroxyl benzylpiperazine (4-OH BZP) and 3 0 -hydroxyl benzylpiperazine (3- OH BZP) was custom synthesised by Sigma Aldrich (New Zealand) and used to quantify the levels of these metabolites. The purity of all standards was verified by LCMS. 2.2. Sample handling Blood samples (6 mL) were collected in heparinised tubes and allowed to stand at room temperature for 30 min prior to centrifugation at 3000 rpm for 15 min to separate the plasma and red blood cell fractions. An aliquot of plasma (100 mL) was Forensic Science International 186 (2009) 63–67 ARTICLE INFO Article history: Received 13 October 2008 Received in revised form 14 January 2009 Accepted 16 January 2009 Available online 3 March 2009 Keywords: BZP Pharmacokinetics Plasma Urine Metabolites ABSTRACT There have been many reports of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) being used as recreational drugs which have been widely marketed in the form of ‘party pills’ since the late 1990’s. However, there is no information currently available describing the pharmacokinetics of these drugs in humans. Human plasma concentrations of BZP were measured in blood and urine samples taken from healthy adults (n = 7) over 24 h following a 200 mg oral dose of BZP. Plasma concentrations of BZP were found to peak at 262 ng/mL (C max ) and 75 min (T max ). Plasma concentrations of the major metabolites of BZP, 4-OH BZP and 3-OH BZP, were found to peak at 7 ng/mL (at 60 min) and 13 ng/mL (at 75 min) respectively. The elimination half-life (t 1/2 ) for BZP was found to be 5.5 h. Clearance (Cl/F) was found to be 99 L/h. The results of this study indicate that BZP may be detectable in plasma for up to 30 h following an oral dose. Additionally, several urinary metabolites can be detected. ß 2009 Elsevier Ireland Ltd. All rights reserved. * Corresponding author. Tel.: +649 373 7599x82329; fax: +649 367 7192. E-mail address: u.antia@auckland.ac.nz (U. Antia). Contents lists available at ScienceDirect Forensic Science International journal homepage: www.elsevier.com/locate/forsciint 0379-0738/$ – see front matter ß 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.forsciint.2009.01.015