Daniel Władysława A, Kot Marta, Wójcikowski Jacek
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Pol J Pharmacol. 2003 Nov-Dec;55(6):1045-53.
Caffeine undergoes 3-N-demethylation via CYP1A2, as well as 1-N-demethylation, 7-N-demethylation and 8-hydroxylation, which may involve other CYP isoenzymes. The aim of the present study was to investigate the influence of clomipramine, desipramine, sertraline, nefazodone and mirtazapine on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated antidepressants, with an exception of mirtazapine, added in vitro to liver microsomes had an inhibitory effect on caffeine metabolism (via competitive or mixed mechanism), though their potency towards particular metabolic pathways was different. Dixon analysis of caffeine metabolism carried out in the control liver microsomes, in the absence and presence of the antidepressant drugs showed that desipramine and clomipramine exerted the most potent inhibitory effect on caffeine metabolism. Desipramine decreased the rates of 1-N-, 3-N- and 7-N-demethylations, and 8-hydroxylation of caffeine (Ki = 23.3, 36.6, 23.3 and 63.3 microM, respectively), the effect on 1-N- and 7-N-demethylation being the most pronounced. Clomipramine showed distinct inibition of 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine, the effects on N-demethylations being the most pronounced (Ki = 38.6, 34.8, 45.6 microM, respectively). Its effect on 7-N-demethylation was rather weak (Ki = 97.8 microM). Sertraline decreased significantly the rate of 1-N- and 3-N-demethylation and 8-hydroxylation (Ki = 37.3, 69.3 and 64 microM, respectively), while its effect on 7-N-demethylation of caffeine was less pronounced (Ki = 92.1 microM). Nefazodone displayed clear effect on 3-N- and 7-N-demethylation (Ki = 68.8 and 66.4 microM, respectively), but was weak in inhibiting 1-N-demethylation and 8-hydroxylation of caffeine (Ki = 110 and 186 microM, respectively). In contrast to the above-tested antidepressants, mirtazapine did not decrease significantly the oxidation rates of 3-N-demethylation or 8-hydroxylation (Ki = 264 and 455 microM, respectively) and had no effect on other oxidation pathways of caffeine. In summary, we have observed intra- and inter-drug differences in the inhibitory effects of the antidepressants on the four oxidation pathways of caffeine in rat liver microsomes. The tested antidepressants (with an exception of mirtazapine) may lead to drug-drug metabolic interactions at a level of a few CYP isoforms. The obtained results provide further indirect evidence that apart from CYP1A2, other CYP isoforms are also important for the metabolism of caffeine.
咖啡因通过CYP1A2进行3 - N - 去甲基化，以及1 - N - 去甲基化、7 - N - 去甲基化和8 - 羟基化，这可能涉及其他CYP同工酶。本研究的目的是研究氯米帕明、地昔帕明、舍曲林、奈法唑酮和米氮平对大鼠肝微粒体中通过咖啡因氧化测定的细胞色素P - 450活性的影响。所得结果表明，除米氮平外，所有体外添加到肝微粒体中的被研究抗抑郁药均对咖啡因代谢有抑制作用（通过竞争性或混合机制），尽管它们对特定代谢途径的效力不同。在对照肝微粒体中，在不存在和存在抗抑郁药的情况下对咖啡因代谢进行的狄克逊分析表明，地昔帕明和氯米帕明对咖啡因代谢的抑制作用最强。地昔帕明降低了咖啡因的1 - N - 、3 - N - 和7 - N - 去甲基化以及8 - 羟基化速率（Ki分别为23.3、36.6、23.3和63.3 microM），对1 - N - 和7 - N - 去甲基化的影响最为明显。氯米帕明对咖啡因的1 - N - 和3 - N - 去甲基化以及8 - 羟基化有明显抑制作用，对N - 去甲基化的影响最为明显（Ki分别为38.6、34.8、45.6 microM）。其对7 - N - 去甲基化的影响较弱（Ki = 97.8 microM）。舍曲林显著降低了1 - N - 和3 - N - 去甲基化以及8 - 羟基化速率（Ki分别为37.3、69.3和64 microM），而其对咖啡因7 - N - 去甲基化的影响不太明显（Ki = 92.1 microM）。奈法唑酮对3 - N - 和7 - N - 去甲基化有明显作用（Ki分别为68.8和66.4 microM），但对咖啡因的1 - N - 去甲基化和8 - 羟基化抑制作用较弱（Ki分别为110和186 microM）。与上述测试的抗抑郁药相反，米氮平没有显著降低3 - N - 去甲基化或8 - 羟基化的氧化速率（Ki分别为264和455 microM），并且对咖啡因的其他氧化途径没有影响。总之，我们观察到抗抑郁药对大鼠肝微粒体中咖啡因的四种氧化途径的抑制作用存在药物内和药物间差异。所测试的抗抑郁药（米氮平除外）可能在几种CYP同工酶水平上导致药物代谢相互作用。所得结果提供了进一步的间接证据，表明除CYP1A2外，其他CYP同工酶对咖啡因的代谢也很重要。
