Investigations on the cytochrome P450 (CYP) isoenzymes involved in the metabolism of the designer drugs N-(1-phenyl cyclohexyl)-2-ethoxyethanamine and N-(1-phenylcyclohexyl)-2-methoxyethanamine.
Investigations using insect cell microsomes with cDNA-expressed human cytochrome P450 (CYP)s and human liver microsomes (HLM) are reported on the CYP isoenzymes involved in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) to O-deethyl PCEEA and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA) to O-demethyl PCMEA. Gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry was used for the analysis of the incubation samples. PCEEA O-deethylation was catalyzed by CYP2B6, CYP2C9, CYP2C19, and CYP3A4, while PCMEA O-demethylation was catalyzed only by CYP2B6 and CYP2C19. Considering the relative activity factor approach, these enzymes accounted for 53%, 25%, 4%, and 18% of net clearance for PCEEA and 91% and 9% of net clearance for PCMEA, respectively. The chemical CYP2B6 inhibitor 4-(4-chlorobenzyl)pyridine (CBP) reduced the metabolite formation in pooled HLM by 63% at 1 microM PCEEA. At 10 microM PCEEA, CBP reduced metabolite formation by 61%, while inhibition of CYP3A4 by ketoconazole and inhibition of CYP2C9 by sulfaphenazole showed no inhibitory effect. At 1 microM PCMEA, CBP reduced metabolite formation in pooled HLM by 70% and at 10 microM PCMEA by 78%, respectively. In conclusion, the main metabolic step of both studied drugs was catalyzed by different CYPs.
Sauer
Christoph
C
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, Kirrberger Strasse 1, D-66421 Homburg (Saar), Germany.
Peters
Frank T
FT
Schwaninger
Andrea E
AE
Meyer
Markus R
MR
Maurer
Hans H
HH
D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015198:Designer Drugs / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D007527:Isoenzymes / Q000378:metabolism*; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism
D015198:Designer Drugs; D007527:Isoenzymes; C529456:N-(1-phenylcyclohexyl)-2-ethoxyethanamine; C529457:N-(1-phenylcyclohexyl)-2-methoxyethanamine; D003577:Cytochrome P-450 Enzyme System; D010622:Phencyclidine