Wikell C, Bergqvist P B, Hjorth S, Apelqvist G, Björk H, Bengtsson F
Department of Clinical Pharmacology, Lund University, Sweden.
Clin Neuropharmacol. 1998 Sep-Oct;21(5):296-306.
Venlafaxine (VEN) pharmacokinetics and effects on the brain monoamine output were investigated in the context of experimental hepatic encephalopathy (HE). Systemic VEN (10 mg/kg; subcutaneous) was administered to chronic portacaval shunted (PCS) and sham-operated rats. Their neocortical extracellular levels of 5-HT, 5-HIAA, NA, and DA were then assessed using microdialysis. Serum, brain extracellular, and brain tissue levels of racemic VEN and its main metabolites were also investigated. In a dose-equipotent manner, the VEN challenge increased the 5-HT levels in PCS rats compared with VEN-treated controls, whereas the 5-HIAA levels decreased similarly with time after the challenge in PCS and controls. Brain extracellular NA levels increased similarly in PCS and controls after VEN, but DA increased predominantly in controls. A similar single dose challenge resulted in clearly higher VEN levels in serum, brain extracellular fluid, and brain tissue in the PCS rats compared with controls. However, the VEN brain tissue/serum ratios were in the same order of magnitude for the two groups. Of the main VEN metabolites, only O-desmethylvenlafaxine (ODV) could be detected in pharmacologically significant amounts. The ODV concentration was also elevated in all three investigated biomatrices of the PCS rats versus control rats. The authors concluded that a typical novel brain monoamine-acting drug, such as VEN, exhibits both pharmacokinetic and pharmacodynamic alterations in experimental HE. Accordingly, the results of this study suggest that this frequently used type of drug should be further studied for its potential combined kinetic/dynamic actions in compromised patients with liver impairment.
在实验性肝性脑病（HE）的背景下，研究了文拉法辛（VEN）的药代动力学及其对脑单胺输出的影响。对慢性门腔分流（PCS）大鼠和假手术大鼠皮下注射全身性VEN（10 mg/kg）。然后使用微透析评估它们新皮质细胞外5-羟色胺（5-HT）、5-羟吲哚乙酸（5-HIAA）、去甲肾上腺素（NA）和多巴胺（DA）的水平。还研究了消旋VEN及其主要代谢物的血清、脑细胞外液和脑组织水平。与VEN治疗的对照组相比，VEN激发以等效剂量方式增加了PCS大鼠的5-HT水平，而在PCS大鼠和对照组中，激发后5-HIAA水平随时间同样下降。VEN给药后，PCS大鼠和对照组的脑细胞外NA水平同样升高，但DA主要在对照组中升高。与对照组相比，类似的单剂量激发导致PCS大鼠血清、脑细胞外液和脑组织中的VEN水平明显更高。然而，两组的VEN脑组织/血清比值处于相同的数量级。在主要的VEN代谢物中，仅能检测到药理活性显著的O-去甲基文拉法辛（ODV）。与对照大鼠相比，PCS大鼠所有三个研究生物基质中的ODV浓度也升高。作者得出结论，一种典型的新型脑单胺作用药物，如VEN，在实验性HE中表现出药代动力学和药效学改变。因此，本研究结果表明，这种常用类型的药物应进一步研究其在肝功能受损的患者中的潜在联合动力学/动态作用。
