STUDIES ON THE METABOLISM OF HALOPERIDOL (HP) - THE ROLE OF CYP3A IN THE PRODUCTION OF THE NEUROTOXIC PYRIDINIUM METABOLITE HPP+ FOUND IN RAT-BRAIN FOLLOWING IP ADMINISTRATION OF HP
STUDIES ON THE METABOLISM OF HALOPERIDOL (HP) - THE ROLE OF CYP3A IN THE PRODUCTION OF THE NEUROTOXIC PYRIDINIUM METABOLITE HPP+ FOUND IN RAT-BRAIN FOLLOWING IP ADMINISTRATION OF HP
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DOI：
10.1016/0024-3205(95)02240-5
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发表时间：
1995-11-17
期刊：
影响因子：
6.1
通讯作者：
CASTAGNOLI, N
中科院分区：
文献类型：
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作者：
IGARASHI, K;KASUYA, F;CASTAGNOLI, N
对腹腔注射 HP (10 mg/kg) 的大鼠的血浆和脑组织中氟哌啶醇 [HP] 及其吡啶鎓代谢物 HPP+ 的水平进行了评估。给药后 0-3 小时内，血浆中 HP 和 HPP+ 水平线性下降。另一方面，同期脑组织中HPP+水平逐渐升高。当连续三天注射 HP (10 mg/kg) 时，脑组织中的 HPP+ 水平进一步增加。还在大鼠脑线粒体和肝微粒体制剂中研究了 HPP+ 的形成。在脑线粒体中未发现负责将 HP 转化为 HPP+ 的酶活性。肝微粒体酶以大致相同的效率催化 HP 及其四氢吡啶脱水产物 HPTP 氧化为 HPP+。采用多种细胞色素 P450 抑制剂和抗细胞色素 P450 抗体进行的研究旨在鉴定负责催化 HP 和 HPTP 氧化为 HPP+ 的细胞色素 P450 的形式。酮康唑和硝苯地平以及抗 CYP3A 抗体强烈抑制肝微粒体中 HPP+ 的形成。这些结果表明，大鼠肝微粒体中 HP 和 HPTP 形成 HPP+ 主要由 CYP3A 催化，但不能排除其他 P450 形式的参与。
The levels of haloperidol [HP] and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated ip with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ levels in brain tissues increased gradually during the same period. HPP+ levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP+ also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ with about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out.