Daniel W A, Syrek M, Haduch A
Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343, Cracow, Poland.
Eur Neuropsychopharmacol. 2002 Oct;12(5):371-7. doi: 10.1016/s0924-977x(02)00053-6.
The aim of the present study was to determine optimum conditions for studying promazine and perazine metabolism in rat liver microsomes, and to investigate the influence of specific cytochrome P-450 inhibitors on 5-sulfoxidation and N-demethylation of these neuroleptics. Based on the developed method, the metabolism of neuroleptics in liver microsomes was studied at linear dependence of product formation on time, and protein and substrate concentrations (incubation time: 10 min; concentration of microsomal proteins: promazine-0.7 mg ml(-1), perazine-0.5 mg ml(-1); substrate concentrations: promazine-25, 40 and 75 nmol ml(-1), perazine-20, 35, 50 nmol ml(-1)). A Dixon analysis of the metabolism of neuroleptics showed that quinine (a CYP2D1 inhibitor), metyrapone (a CYP2B1/B2 inhibitor) and alpha-naphthoflavone (a CYP1A1/2 inhibitor) affected, whereas erythromycin (a CYP3A inhibitor) and sulfaphenazole (a CYP2C inhibitor) did not change the neuroleptic biotransformation. N-Demethylation of promazine was competitively inhibited by quinine (K(i)=20 microM) and metyrapone (K(i)=83 microM), while that of perazine-by quinine (K(i)=46.5 microM), metyrapone (K(i)=46 microM) and alpha-naphthoflavone (K(i)=78.8 microM). 5-Sulfoxidation of promazine was inhibited only by quinine (K(i)=28.6 microM), whereas that of perazine-by quinine (K(i)=10 microM) and metyrapone (K(i)=96 microM). The results obtained are compared with our previous findings of analogous experiments concerning thioridazine, and with the data on other phenothiazines and species. In summary, it is proposed that N-demethylation of the mentioned phenothiazine neuroleptics in the rat is catalyzed by the isoenzymes CYP2D1, CYP2B2 and CYP1A2 (CYP1A2 does not refer to promazine). 5-Sulfoxidation of these drugs may be mediated by different isoenzymes, e.g. CYP2D1 (promazine and perazine), CYP2B2 (perazine) and CYP1A2 (thioridazine). Isoenzymes belonging to subfamilies CYP2C and CYP3A do not seem to be involved in the metabolism of the investigated neuroleptics in the rat. The results obtained point to the drug structure and species differences in the contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazines.
本研究的目的是确定在大鼠肝微粒体中研究丙嗪和奋乃静代谢的最佳条件，并研究特定细胞色素P-450抑制剂对这些抗精神病药物5-硫氧化和N-去甲基化的影响。基于所建立的方法，在产物形成与时间、蛋白质和底物浓度呈线性关系的条件下研究了肝微粒体中抗精神病药物的代谢（孵育时间：10分钟；微粒体蛋白浓度：丙嗪-0.7mg/ml，奋乃静-0.5mg/ml；底物浓度：丙嗪-25、40和75nmol/ml，奋乃静-20、35、50nmol/ml）。对抗精神病药物代谢的Dixon分析表明，奎宁（一种CYP2D1抑制剂）、美替拉酮（一种CYP2B1/B2抑制剂）和α-萘黄酮（一种CYP1A1/2抑制剂）有影响，而红霉素（一种CYP3A抑制剂）和磺胺苯吡唑（一种CYP2C抑制剂）未改变抗精神病药物的生物转化。丙嗪的N-去甲基化受到奎宁（K(i)=20μM）和美替拉酮（K(i)=83μM）的竞争性抑制，而奋乃静的N-去甲基化受到奎宁（K(i)=46.5μM）、美替拉酮（K(i)=46μM）和α-萘黄酮（K(i)=78.8μM）的抑制。丙嗪的5-硫氧化仅受到奎宁（K(i)=28.6μM）抑制，而奋乃静的5-硫氧化受到奎宁（K(i)=10μM）和美替拉酮（K(i)=96μM）的抑制。将所得结果与我们先前关于硫利达嗪类似实验的结果以及其他吩噻嗪类药物和物种的数据进行了比较。总之，提出大鼠中上述吩噻嗪类抗精神病药物的N-去甲基化由同工酶CYP2D1、CYP2B2和CYP1A2催化（CYP1A2不适用于丙嗪）。这些药物的5-硫氧化可能由不同的同工酶介导，例如CYP2D1（丙嗪和奋乃静）、CYP2B2（奋乃静）和CYP1A2（硫利达嗪）。属于CYP2C和CYP3A亚家族的同工酶似乎不参与大鼠中所研究抗精神病药物的代谢。所得结果表明细胞色素P-450同工酶对吩噻嗪类药物代谢的贡献存在药物结构和物种差异。
