Gex-Fabry M, Balant-Gorgia A E, Balant L P, Garrone G
Department of Psychiatry, University of Geneva, Switzerland.
Clin Pharmacokinet. 1990 Sep;19(3):241-55. doi: 10.2165/00003088-199019030-00007.
A steady-state model is here developed as a framework for the analysis of blood concentrations of clomipramine, obtained during routine drug monitoring. A model is proposed to account for its major metabolic pathways, hydroxylation and demethylation, including first-pass effect. Impaired hydroxylation capacity is shown to lead to a dramatic increase in the concentration of demethyl-clomipramine, with a concomitant moderate increase in that of the parent drug. Deficient demethylation capacity is associated with a reduced ratio of demethyl metabolite to parent drug. A nomogram is provided to allow easy determination of hydroxylation and demethylation capacities from routinely measured blood concentrations. Data from 150 patients are analysed in order to identify interindividual variability factors. Average pseudo-clearances, calculated from trough blood concentrations at steady-state, are 17 L/h for hydroxylation, 23 L/h for demethylation and 40 L/h for elimination of hydroxylated metabolites. Maximum to minimum ratios are 8, 27 and 11, respectively. The metabolising capacity through either process significantly decreases with increasing age, clearance estimates being 40 to 50% lower for patients 75 years or older than for those 40 years or younger. Tobacco smoking and chronic alcohol consumption induce and reduce the demethylation clearance, respectively. Inhibition of hydroxylation in the presence of phenothiazine comedication is also shown. Finally, small but significant differences according to sex are observed. Potential implications of the proposed model-based approach include adaptation of the dosage regimen to individual characteristics at the very beginning of antidepressant therapy, and early detection of patients with impaired metabolising capacities.
本文建立了一个稳态模型，作为分析常规药物监测期间获得的氯米帕明血药浓度的框架。提出了一个模型来解释其主要代谢途径，即羟基化和去甲基化，包括首过效应。研究表明，羟基化能力受损会导致去甲基氯米帕明浓度急剧增加，同时母体药物浓度适度增加。去甲基化能力不足与去甲基代谢物与母体药物的比例降低有关。提供了一个列线图，以便根据常规测量的血药浓度轻松确定羟基化和去甲基化能力。分析了150名患者的数据，以确定个体间的变异因素。根据稳态时的谷血药浓度计算的平均伪清除率，羟基化清除率为17L/h，去甲基化清除率为23L/h，羟基化代谢物消除清除率为40L/h。最大与最小比值分别为8、27和11。随着年龄的增长，通过这两种过程的代谢能力显著下降，75岁及以上患者的清除率估计比40岁及以下患者低40%至50%。吸烟和长期饮酒分别诱导和降低去甲基化清除率。同时也显示了在联合使用吩噻嗪时对羟基化的抑制作用。最后，观察到了根据性别存在的微小但显著的差异。所提出的基于模型的方法的潜在意义包括在抗抑郁治疗开始时根据个体特征调整给药方案，以及早期发现代谢能力受损的患者。
