Center for Psychopharmacology, Diakonhjemmet Hospital, School of Pharmacy, University of Oslo, Oslo, Norway.
Ther Drug Monit. 2012 Oct;34(5):512-7. doi: 10.1097/FTD.0b013e3182693d2a.
Preliminary reports have indicated that valproic acid (VPA) reduces serum concentrations of olanzapine (OLZ). The aim of this study was to investigate the impact of VPA and other antiepileptic drugs (AEDs) on serum concentrations of OLZ and 3 of its major metabolites in a large-scale material of therapeutic drug monitoring samples.
OLZ-treated patients were stratified into subgroups according to coadministration of various AEDs, that is, lamotrigine (LTG; 110 patients/153 samples), VPA (92/166), LTG + VPA (7/12), carbamazepine (CBZ) (8/8), oxcarbazepine (2/3), gabapentin (3/4), levetiracetam (2/3), and topiramate (2/2). A control group treated with OLZ without AEDs was also included (205/247). Dose-adjusted serum concentrations (C:D ratios) of OLZ and its major metabolites (N-desmethyl, N-oxide, and 10-N-glucuronide) were compared between AED subgroups and controls, using linear mixed model analyses with age, gender, and cigarette smoking as covariates.
Significantly lower OLZ C:D ratios were found in patients comedicated with VPA (-32%, P < 0.001), VPA + LTG (-31%, P < 0.01), and CBZ (-50%, P < 0.001), compared with controls. The 10-N-glucuronide concentration was significantly lower in patients comedicated with VPA (-26%, P < 0.001), whereas CBZ significantly lowered N-desmethyl (-42%, P = 0.001) and N-oxide (-52%, P < 0.001) metabolite concentrations. C:D ratios of OLZ and metabolites were not significantly affected by comedication with LTG or any of the other AEDs. All covariates were significant determinants of OLZ C:D ratio, that is, age 60 years or above +35% (P < 0.001), female gender +11% (P < 0.01) and smoking -32% (P < 0.001).
Concurrent use of VPA significantly decreases serum concentrations of OLZ to an extent comparable with smoking. The mechanism behind the interaction could not be derived from the results of this study.
初步报告表明，丙戊酸（VPA）降低奥氮平（OLZ）的血清浓度。本研究的目的是在大规模治疗药物监测样本中，研究 VPA 和其他抗癫痫药物（AEDs）对 OLZ 及其 3 种主要代谢物血清浓度的影响。
根据联合使用各种 AED 的情况，将 OLZ 治疗患者分为亚组，即拉莫三嗪（LTG；110 例/153 例）、VPA（92/166）、LTG+VPA（7/12）、卡马西平（CBZ）（8/8）、奥卡西平（2/3）、加巴喷丁（3/4）、左乙拉西坦（2/3）和托吡酯（2/2）。还包括一组未使用 AED 治疗 OLZ 的对照组（205/247）。使用线性混合模型分析，将年龄、性别和吸烟作为协变量，比较 AED 亚组和对照组之间 OLZ 及其主要代谢物（N-去甲基、N-氧化物和 10-N-葡萄糖醛酸苷）的剂量调整后血清浓度（C:D 比值）。
与对照组相比，合并使用 VPA（-32%，P <0.001）、VPA+LTG（-31%，P <0.01）和 CBZ（-50%，P <0.001）的患者 OLZ C:D 比值显著降低。合并使用 VPA 的患者 10-N-葡萄糖醛酸苷浓度降低（-26%，P <0.001），而 CBZ 显著降低 N-去甲基（-42%，P =0.001）和 N-氧化物（-52%，P <0.001）代谢物浓度。合并使用 LTG 或任何其他 AED 对 OLZ 和代谢物的 C:D 比值没有显著影响。所有协变量都是 OLZ C:D 比值的重要决定因素，即 60 岁或以上年龄增加 35%（P <0.001）、女性增加 11%（P <0.01）和吸烟减少 32%（P <0.001）。
同时使用 VPA 可显著降低 OLZ 的血清浓度，程度与吸烟相当。这种相互作用的机制无法从本研究的结果中推导出来。
