Tennison M B, Miles M V, Pollack G M, Thorn M D, Dupuis R E
Department of Neurology, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7025.
Epilepsia. 1988 Sep-Oct;29(5):543-7. doi: 10.1111/j.1528-1157.1988.tb03758.x.
Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4-en-VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4-en-VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4-en-VPA correlated with older age and absence of encephalopathy. 4-en-VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2-en-VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4-en-VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4-en-VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4-en-VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was detected only in patients receiving polytherapy, a potent risk factor for developing this rare complication.
特发性肝毒性虽然罕见，但在使用丙戊酸盐（VPA）治疗患者时是一个主要问题。有几个临床标准与发生这种并发症的风险增加相关，但需要更具体的预测指标。据推测，4-烯丙戊酸（4-en-VPA）或其进一步的代谢产物之一可能是肝毒性的原因，并且在某些情况下，VPA的代谢会转向该产物。我们推测，测量血清中4-en-VPA或另一种代谢产物的浓度可能是一种简单的技术，可预测发生特发性肝毒性的风险。由于这种并发症很罕见，我们选择通过多元线性回归模型分析我们的数据，探索VPA或其三种代谢产物与肝毒性临床风险因素之间的关联。4-en-VPA与年龄较大和无脑病相关。4-en-VPA仅在接受联合治疗的患者中出现；所有患者也在接受卡马西平（CBZ）治疗。2-烯丙戊酸（2-en-VPA）与营养状况差相关。我们得出结论，常规测量血清4-en-VPA不太可能成为发生致命肝毒性风险的有用预测指标。4-en-VPA的血清浓度可能无法反映其在肝脏中的存在或作用，因为它可能会代谢为进一步的中间体或与组织结合。因此，血清中4-en-VPA的水平并不能反映其在肝毒性发病机制中的重要作用。这种代谢产物仅在接受联合治疗的患者中检测到，联合治疗是发生这种罕见并发症的一个有力风险因素。
