Identification of Cytochrome P450 Enzymes Involved in the Metabolism of the Designer Drugs N-(1-Phenylcyclohexyl)-3-ethoxypropanamine and N-(1-Phenylcyclohexyl)-3-methoxypropanamine

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• 作者：Christoph Sauer ; Frank T. Peters ; Andrea E. Schwaninger ; Markus R. Meyer ; Hans H. Maurer
• 刊名：Chemical Research in Toxicology
• 出版年：2008
• 出版时间：October 20, 2008
• 年：2008
• 卷：21
• 期：10
• 页码：1949-1955
• 全文大小：144K
• 年卷期：v.21,no.10(October 20, 2008)
• ISSN：1520-5010

文摘

The involvement of human hepatic cytochrome P450 isoenzymes (P450s) in the metabolism of the designer drugs N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) and N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA) to the common metabolite N-(1-phenylcyclohexyl)-3-hydroxypropanamine (PCHPA) was studied using insect cell microsomes with cDNA-expressed human P450s and human liver microsomes (HLMs). Incubation samples were analyzed by gas chromatography−mass spectrometry or liquid chromatography−mass spectrometry. Among the tested isoenzymes, P450 2B6, P450 2C19, P450 2D6, and P450 3A4 catalyzed PCEPA O-deethylation, and P450 2B6, P450 2C19, and P450 2D6 catalyzed PCMPA O-demethylation. According to the relative activity factor approach, these enzymes accounted for 22, 3, 30, and 45% of the net clearance for PCEPA and 51, 8, and 40% of the net clearance for PCMPA, respectively. At 1 μM PCEPA, the chemical inhibitors 4-(4-chlorobenzyl)pyridine for P450 2B6 and quinidine for P450 2D6 reduced metabolite formation in pooled HLMs by 37 and 73%, respectively, and at 10 μM PCEPA, they reduced metabolite formation by 57 and 26%, respectively. At 1 μM PCMPA, 4-(4-chlorobenzyl)pyridine and quinidine reduced metabolite formation in pooled HLMs by 25 and 39%, respectively, and at 10 μM PCMPA, they reduced metabolite formation by 62 and 27%, respectively. The experiments with the MAB inhibitory to P450 3A4 and the chemical inhibitor ketoconazole for P450 3A4 showed no inhibitory effect concerning PCEPA O-dealkylation. Experiments with HLMs from P450 2D6 poor metabolizers showed a reduction of metabolite formation as compared to pooled HLM of 73 and 25% (1 μM and 10 μM PCEPA) and 40 and 38% (1 μM and 10 μM PCMPA), respectively. In conclusion, the main metabolic step was catalyzed by different P450s.