3种碳青霉烯类药物对重症感染合并癫痫患者丙戊酸钠血药浓度影响及其与肝肾功能相关性

目的：分析美罗培南、亚胺培南、比阿培南对重症感染合并癫痫患者丙戊酸钠（VPA）谷浓度影响，探讨患者肝、肾功能对其降低作用的影响。方法：回顾性分析某院2012年1月-2018年5月113例接受VPA与碳青霉烯类抗菌药联用治疗重症感染合并癫痫的患者病例资料，比较美罗培南、亚胺培南、比阿培南对患者VPA谷浓度影响；另按患者Child-Pughp评分、内生肌酐清除率情况分组，分析肝功能、肾功能对两药联用后丙戊酸钠谷浓度的影响。结果：美罗培南、亚胺培南、比阿培南能显著降低联用后患者丙戊酸钠谷浓度（P < 0.05），美罗培南组、亚胺培南组、比阿培南组平均降低幅度分别为：61.90%±5.12%，43.51%±3.95%，70.12%±3.46%，平均降低幅度顺序为：比阿培南 > 美罗培南 > 亚胺培南；与肝功能正常组比较，轻度肝损伤组、中-重度肝损伤组患者丙戊酸钠谷浓度明显增高，降幅由52.71%~79.34%降低至30.00%~46.36%（P < 0.05）；与肾功能正常组比较，轻度肾损伤患者丙戊酸钠浓度无明显差异（P > 0.05），中-重度肾损伤组患者丙戊酸钠血药浓度增高，分别由20.16~40.28 μg·mL^-1增高至30.15~50.62 μg·mL^-1（P < 0.05），但降幅无明显差异（P > 0.05）。结论：美罗培南、亚胺培南、比阿培南均能显著降低联用后丙戊酸钠血药浓度，肝功能损伤能明显降低这种作用，肾功能损伤则对这种作用的影响不明显，提示碳青霉烯类药物与丙戊酸钠的药动学相互作用主要在肝脏。

The influence of hepatic and renal function on reduction of plasma concentration of sodium valproate by carbapenem drugs

OBJECTIVE To analyze the effect of meropenem, imipenem and biapenem on valproate sodium (VPA) trough concentration in patients with severe infection and epilepsy, and to explore the influence of liver and renal function on its lowering effect. METHODS The data of 113 patients with severe infection and epilepsy who were treated with VPA and carbapenem antibiotics in our hospital from January 2012 to May 2018 were retrospectively analyzed. The effects of liver function and renal function on trough valproate concentrations were analyzed according to the Child-Pughp score and endogenous creatinine clearance rate. RESULTS Meropenem, imipenem and biapenem could significantly reduce the valproate trough concentration (P < 0.05). The mean decrease of meropenem, imipenem and biapenem were 61.90%±5.12%, 43.51%±3.95, 70.1,2%±3.46%,respectively. The order of decreasing amplitude:Biapenem > Meropenem > Imipenem. Compared with the normal liver function group, the trough concentration of VPA were significantly higher in the group with mild, moderate and sever liver impairment (P < 0.05), and the plasma concentration of VPA decreased from 52.71%-79.34% to 30.00%-46.36%. Compared with the normal renal function group, there was no significant change in the trough concentration of VPA in patients with mild renal impairment, and it increased from 20.16-40.28 to 30.15-50.62 μg·mL^-1(P < 0.05). CONCLUSION The combination of three carbapenem drugs and VPA significantly reduced the trough concentration of VPA. The reduction of VPA concentration was restored by liver impairment, and renal impairment has no significant impact on it. Results suggest that the pharmacokinetic interaction between carbapenem drugs and VPA mainly occur in the liver.