In vivo metabolism of the new designer drug 1-(4-methoxyphenyl)piperazine (MeOPP) in rat and identification of the human cytochrome P450 enzymes responsible for the major metabolic step

Abstract

1. The in vivo metabolism of 1-(4-methoxyphenyl)piperazine (MeOPP), a novel designer drug, was studied in male Wistar rats.

2. MeOPP was mainly O-demethylated to 1-(4-hydroxyphenyl)piperazine (4-HO-PP) in addition to degradation of the piperazine moiety.

3. O-demethylation, the major metabolic step, was studied with cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes in pooled human liver microsomes (pHLM) and in single donor human liver microsomes with CYP2D6 poor metabolizer genotype (PM HLM).

4. CYP2D6 catalysed O-demethylation with apparent K_m and V_max values of 48.34 ± 14.48 µM and 5.44 ± 0.47 pmol min⁻¹ pmol⁻¹ CYP, respectively. pHLM catalysed the monitored reaction with an apparent K_m = 204.80 ± 51.81 µM and V_max = 127.50 ± 13.25 pmol min⁻¹ mg⁻¹ protein.

5. The CYP2D6-specific chemical inhibitor quinidine (1 and 3 µM) significantly inhibited 4-HO-PP formation by 71.9 ± 4.8% and by 98.5% ± 0.5%, respectively, in incubation mixtures with pHLM and 200 µM MeOPP.

6. O-demethylation was significantly lower in PM HLM compared with pHLM (70.6% ± 7.2%).

7. These data suggest that polymorphically expressed CYP2D6 is the enzyme mainly responsible for MeOPP O-demethylation.