Svinarov D A, Pippenger C E
Department of Clinical Laboratory, Alexander Hospital, Sofia, Bulgaria.
Ther Drug Monit. 1995 Jun;17(3):217-20.
Steady state plasma carbamazepine (CBZ), carbamazepine epoxide (CBZE), and carbamazepine diol (CBZD) concentrations were quantified by HPLC in 121 specimens obtained from two groups of epileptic patients: 78 receiving CBZ monotherapy (I), and 43 receiving CBZ and valproic acid (VPA) (II). The differences of drug/metabolite ratios and concentration/dose (mumol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of VPA on CBZ metabolism. Results as means +/- SD were CBZ/CBZE 5.85 +/- 3.91 (I) vs. 4.22 +/- 1.57 (II), p < 0.02; CBZ/CBZD 2.94 +/- 1.94 (I) vs. 2.82 +/- 1.15 (II); CBZE/CBZD 0.53 +/- 0.24 (I) vs. 0.71 +/- 0.32 (II), p < 0.001. Concentration/dose ratios: CBZ 2.32 +/- 1.58 (I) vs. 3.04 +/- 1.41 (II), p < 0.05; CBZE 0.41 +/- 0.20 (I) vs. 0.73 +/- 0.28 (II), p < 0.001; CBZD 0.82 +/- 0.35 (I) vs. 1.22 +/- 0.70 (II), p < 0.001. Drug/metabolite relationship data seem to support the concept for VPA as a selective inhibitor of epoxide hydrolase, but concentration/dose ratios indicate a reduced clearance for the parent drug, and especially for its two metabolites. This latter finding is in a controversy with the former concept. In addition, a considerable age-dependency of the influence of VPA on CBZ metabolism was found: compared to monotherapy, drug/metabolite and concentration/dose ratios were most changed in children. We assume that VPA is probably not a selective inhibitor of epoxide hydrolase, and affects nonspecifically all steps of the epoxide-diol pathway of CBZ metabolism.
采用高效液相色谱法（HPLC）对121份来自两组癫痫患者的样本进行稳态血浆卡马西平（CBZ）、卡马西平环氧化物（CBZE）和卡马西平二醇（CBZD）浓度的定量分析：78例接受CBZ单药治疗（I组），43例接受CBZ与丙戊酸（VPA）联合治疗（II组）。计算药物/代谢物比率和浓度/剂量（μmol/L/mg/kg/天或1/清除率）比率的差异，以此作为VPA对CBZ代谢影响的衡量指标。结果以均值±标准差表示，CBZ/CBZE为5.85±3.91（I组）对4.22±1.57（II组），p<0.02；CBZ/CBZD为2.94±1.94（I组）对2.82±1.15（II组）；CBZE/CBZD为0.53±0.24（I组）对0.71±0.32（II组），p<0.001。浓度/剂量比率：CBZ为2.32±1.58（I组）对3.04±1.41（II组），p<0.05；CBZE为0.41±0.20（I组）对0.73±0.28（II组），p<0.001；CBZD为0.82±0.35（I组）对1.22±0.70（II组），p<0.001。药物/代谢物关系数据似乎支持VPA作为环氧化物水解酶选择性抑制剂的概念，但浓度/剂量比率表明母体药物及其两种代谢物的清除率降低。后一发现与前一概念存在争议。此外，还发现VPA对CBZ代谢的影响存在显著的年龄依赖性：与单药治疗相比，儿童组的药物/代谢物和浓度/剂量比率变化最大。我们推测VPA可能不是环氧化物水解酶的选择性抑制剂，而是非特异性地影响CBZ代谢中环氧化物 - 二醇途径的所有步骤。
