Kugelberg F C, Apelqvist G, Carlsson B, Ahlner J, Bengtsson F
Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
Br J Pharmacol. 2001 Apr;132(8):1683-90. doi: 10.1038/sj.bjp.0704015.
The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted. By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed. In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg(-1) day(-1) were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions. In the group treated with 100 mg kg(-1) day(-1), the serum and brain total CIT levels were found to be 20 times and 6 - 8 times higher than in the rats treated with 10 or 20 mg kg(-1) day(-1), respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum. In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed. In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.
抗抑郁药西酞普兰（CIT）属于选择性5-羟色胺再摄取抑制剂（SSRI），目前在精神病学中广泛应用。非常有必要进一步阐明消旋CIT在临床和中毒剂量下对映体选择性分布情况。通过稳态体内模型，利用渗透泵使大鼠进行为期10天的慢性全身暴露，分析了CIT的S-和R-对映体及其代谢产物在血清和两个不同脑区的总量及各自分布情况。在血清中，给予10、20或100mg kg⁻¹天⁻¹的组中，S/R比值分别为0.94、0.83和0.34。脑区中的比值几乎相同。在给予100mg kg⁻¹天⁻¹的组中，血清和脑中CIT的总水平分别比给予10或20mg kg⁻¹天⁻¹的大鼠高20倍和6 - 8倍。在所有组中，脑组织中的CIT水平均高于血清。在自发旷场行为试验中，观察到临床和中毒药物浓度之间存在相关性。总之，当CIT稳态浓度较高时，与S-对映体相比，R-对映体的比例增加。这一点尤其值得关注，因为在体外，S-对映体负责抑制5-羟色胺再摄取。由于对CIT及其主要代谢产物不同的消旋或对映体药物效应的作用部位有了全面了解，目前的数据可能具有重要意义。
