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.
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 Km and Vmax values of 48.34 +/- 14.48 microM and 5.44 +/- 0.47 pmol min(-1) pmol(-1) CYP, respectively. pHLM catalysed the monitored reaction with an apparent Km = 204.80 +/- 51.81 microM and Vmax = 127.50 +/- 13.25 pmol min(-1) mg(-1) protein. 5. The CYP2D6-specific chemical inhibitor quinidine (1 and 3 microM) 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 microM 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.
Staack
R F
RF
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, D-66421 Homberg (Saar), Germany.
Theobald
D S
DS
Paul
L D
LD
Springer
D
D
Kraemer
T
T
Maurer
H H
HH
D000465:Algorithms; D000818:Animals; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D015198:Designer Drugs / Q000378:metabolism* / Q000493:pharmacokinetics; D008401:Gas Chromatography-Mass Spectrometry; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics; D011802:Quinidine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization
D015198:Designer Drugs; D010879:Piperazines; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; C490166:1-(4-methoxyphenyl)piperazine