Svinarov D A, Pippenger C E
Department of Clinical Laboratory, Alexander Hospital, Faculty of Medicine, Sofia, Bulgaria.
Ther Drug Monit. 1996 Dec;18(6):660-5. doi: 10.1097/00007691-199612000-00006.
Steady-state plasma carbamazepine (CBZ), carbamazepine-epoxide (CBZE), and carbamazepine-diol (CBZD) concentrations were quantified by high-performance liquid chromatography in 435 specimens divided into two groups: CBZ monotherapy (n = 78) and CBZ polytherapy (n = 357). Distributions of concentrations of CBZ and its metabolites were derived, their protein binding investigated, and the differences of concentration/dose (mumol/L/mg/kg/day or 1/clearance) ratios were calculated as a measure for the influence of sex, age, and comedication on CBZ metabolism. Concentrations of CBZ ranged from 2.5 to 82.9 mumol/L (mean +/- SD, 22.3 +/- 10.9 mumol/L), 73% being within the therapeutic range (17-51 mumol/L), 24% being less than the therapeutic range, and 3% greater than the therapeutic range. Concentrations of CBZE ranged from 0.85 to 16.6 mumol/L (mean +/- SD, 5.17 +/- 2.56 mumol/L), and those of CBZD were between 0.77 and 36.4 mumol/L (mean +/- SD, 11.3 +/- 5.4 mumol/L). A multiplicative regression best fitted the concentration/dose plots of CBZ and CBZE and an exponential regression for CBZD. Dose correlated best with the second biotransformation product, CBZD. Free fractions were 0.22 +/- 0.03 for CBZ, 0.40 +/- 0.06 for CBZE, and 0.68 +/- 0.11 for CBZD. Sex was found to be of minor importance for CBZ disposition. A gradual, high-amplitude age increase of CBZ dose ratio was observed in the monotherapy group, with global difference of approximately 3.6 times, while CBZE dose ratio increased approximately 2-fold, and CBZD dose ratio increased to the smallest extent of 1.5 times. In the polytherapy group, a smaller global age increase for CBZ dose ratio of 3.4 times was found, but the respective increase for dose ratios of metabolites was greater compared with the monotherapy patients: 2.3 times for CBZE and 1.8 times for CBZD. Comedication of other antiepileptic drugs induced significant decrease of CBZ dose ratio only, but no changes of dose ratios of the metabolites were registered. The influence of valproic acid was represented in a particular pattern. We conclude that these findings could provide valuable information for CBZ metabolism and disposition in epileptic patients with respect to the efforts to ensure the best possible individualization of CBZ therapy.
采用高效液相色谱法对435份样本中的稳态血浆卡马西平（CBZ）、卡马西平 - 环氧化物（CBZE）和卡马西平 - 二醇（CBZD）浓度进行定量分析，这些样本分为两组：CBZ单药治疗组（n = 78）和CBZ联合治疗组（n = 357）。得出了CBZ及其代谢产物的浓度分布，研究了它们的蛋白结合情况，并计算了浓度/剂量（μmol/L/mg/kg/天或1/清除率）比值的差异，以此作为性别、年龄和合并用药对CBZ代谢影响的衡量指标。CBZ浓度范围为2.5至82.9μmol/L（平均值±标准差，22.3±10.9μmol/L），73%在治疗范围内（17 - 51μmol/L），24%低于治疗范围，3%高于治疗范围。CBZE浓度范围为0.85至16.6μmol/L（平均值±标准差，5.17±2.56μmol/L），CBZD浓度在0.77至36.4μmol/L之间（平均值±标准差，11.3±5.4μmol/L）。乘法回归最适合CBZ和CBZE的浓度/剂量图，指数回归适合CBZD的浓度/剂量图。剂量与第二种生物转化产物CBZD的相关性最佳。CBZ的游离分数为0.22±0.03，CBZE为0.40±0.06，CBZD为0.68±0.11。发现性别对CBZ处置的影响较小。在单药治疗组中观察到CBZ剂量比值随年龄逐渐大幅增加，总体差异约为3.6倍，而CBZE剂量比值增加约2倍，CBZD剂量比值增加幅度最小，为1.5倍。在联合治疗组中，CBZ剂量比值的总体年龄增加较小，为3.4倍，但与单药治疗患者相比，代谢产物剂量比值的相应增加更大：CBZE为2.3倍，CBZD为1.8倍。其他抗癫痫药物的联合用药仅导致CBZ剂量比值显著降低，但未观察到代谢产物剂量比值的变化。丙戊酸的影响呈现出特定模式。我们得出结论，这些发现可为癫痫患者的CBZ代谢和处置提供有价值的信息，有助于努力实现CBZ治疗尽可能最佳的个体化。
