کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2601483 1562644 2008 6 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
2,5-Dimethoxyamphetamine-derived designer drugs: Studies on the identification of cytochrome P450 (CYP) isoenzymes involved in formation of their main metabolites and on their capability to inhibit CYP2D6
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
2,5-Dimethoxyamphetamine-derived designer drugs: Studies on the identification of cytochrome P450 (CYP) isoenzymes involved in formation of their main metabolites and on their capability to inhibit CYP2D6
چکیده انگلیسی

The designer drugs 4-methyl-2,5-dimethoxy-amphetamine (DOM), 4-iodo-2,5-dimethoxy-amphetamine (DOI), 4-chloro-2,5-dimethoxy-amphetamine (DOC), 4-bromo-2,5-dimethoxy-amphetamine (DOB), 4-bromo-2,5-dimethoxy-methamphetamine (MDOB), and 2,4,5-trimethoxy-amphetamine (TMA-2) are potent serotonin 5HT2 receptor agonists and have appeared on the illicit drug market. These drugs are mainly metabolized by O-demethylation or in case of DOM by hydroxylation of the methyl moiety. In an initial activity screening using microsomes of insect cells heterologously expressing human CYPs, CYP2D6 was found to be the only CYP isoenzyme involved in the above-mentioned main metabolic steps whereas the amounts of metabolites formed were very small. As inhibition of CYP2D6 by other amphetamines had been described, the inhibitory effects of the 2,5-dimethoxyamphetamine derivatives were studied using insect cell microsomes with heterologously expressed human CYP2D6 and pooled human liver microsomes (HLM) as enzyme sources and dextromethorphan O-demethylation as probe reaction. All studied drugs were observed to be non-mechanism-based competitive inhibitors of CYP2D6 with inhibition constants (Ki) from 7.1 to 296 μM using recombinant CYP2D6 and 2.7–19.9 μM using HLM. For comparison, the Ki values for quinidine and fluoxetine were 0.0092 and 8.2 μM using recombinant CYP2D6 and 0.019 and 0.93 μM using HLM. As the Ki values of the drugs were much higher than that of quinidine and, with the exception of DOI, higher than that of fluoxetine, interactions with other CYP2D6 substrates are possible but rather unlikely.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology Letters - Volume 183, Issues 1–3, 15 December 2008, Pages 52–57
نویسندگان
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