Bergemann Niels, Abu-Tair Fatima, Aderjan Rolf, Kopitz Jürgen
Department of General Psychiatry, University of Heidelberg Voss-Str 4, Heidelberg, Germany.
Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1068-71. doi: 10.1016/j.pnpbp.2007.03.009. Epub 2007 Mar 23.
Up to now direct toxic effects or immunological processes have been said to explain clozapine-induced agranulocytosis. However, more recent studies may suggest that not yet metabolized clozapine is taken up by leukocytes and transformed by oxidative processes to apoptosis-inducing metabolites. To verify this hypothesis the concentrations of clozapine were measured in the plasma and the leukocytes of a patient receiving clozapine who developed clozapine-induced leukocytopenia and in 10 patients receiving clozapine who did not show any serious adverse side effects. The patient who developed leukocytopenia showed clozapine concentrations in the leukocytes that were about 8 times higher than the mean clozapine concentrations in the leukocytes in the group of 10 patients receiving clozapine with no changes in the leukocyte count in the history. However, no major difference was found in the clozapine plasma concentrations. The results may suggest that patients at risk of developing clozapine-induced leukocytopenia show increased clozapine concentrations in the leukocytes although the clozapine plasma concentration is in the therapeutic range. It is assumed that changes or abnormalities of clozapine uptake at the cell membrane might play a role in the development of clozapine-induced leukocytopenia and/or agranulocytosis.
到目前为止，直接毒性作用或免疫过程一直被认为是氯氮平诱导粒细胞缺乏症的原因。然而，最近的研究可能表明，未代谢的氯氮平被白细胞摄取，并通过氧化过程转化为诱导凋亡的代谢产物。为了验证这一假设，我们测量了一名接受氯氮平治疗并出现氯氮平诱导的白细胞减少症患者的血浆和白细胞中的氯氮平浓度，以及10名接受氯氮平治疗但未出现任何严重不良副作用的患者的血浆和白细胞中的氯氮平浓度。出现白细胞减少症的患者白细胞中的氯氮平浓度比10名接受氯氮平治疗且既往白细胞计数无变化的患者组白细胞中氯氮平的平均浓度高约8倍。然而，氯氮平血浆浓度未发现重大差异。结果可能表明，有发生氯氮平诱导白细胞减少症风险的患者，尽管氯氮平血浆浓度在治疗范围内，但白细胞中的氯氮平浓度会升高。据推测，细胞膜上氯氮平摄取量的变化或异常可能在氯氮平诱导的白细胞减少症和/或粒细胞缺乏症的发生中起作用。
