Rakic Ignjatovic Anita, Miljkovic Branislava, Todorovic Dejan, Timotijevic Ivana, Pokrajac Milena
Medicines and Medical Devices Agency of Serbia, Vojvode Stepe No. 458, Belgrade, Serbia.
Br J Clin Pharmacol. 2009 Feb;67(2):199-208. doi: 10.1111/j.1365-2125.2008.03326.x. Epub 2008 Dec 5.
Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders.
VPA does not significantly affect PK or metabolism of MCB at steady state. CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration.
To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients.
Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales.
CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l(-1); 95% confidence interval (CI) -4.84863, -0.66194; P = 0.01] and C(max) by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h(-1) kg(-1); 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l(-1); 95% CI -0.77479, -0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good.
VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB-CBZ PK interaction needs to be further evaluated in a more comprehensive study.
吗氯贝胺（MCB）在体循环前和全身都会经历广泛的代谢，这可能会受到同时使用的药物的影响。丙戊酸（VPA）和卡马西平（CBZ）已被发现可与所有类别的精神药物以及许多其他药物相互作用；VPA是一种广谱抑制剂，而CBZ是多种药物代谢酶的强效诱导剂。以前没有研究旨在调查MCB与VPA或CBZ之间潜在的药代动力学（PK）相互作用；然而，这些药物可能会同时用于治疗抑郁症。
VPA在稳态时对MCB的PK或代谢没有显著影响。CBZ显著降低MCB的暴露量。这种影响是时间依赖性的，在联合给药3 - 5周后更为明显。
评估丙戊酸（VPA）和卡马西平（CBZ）对抑郁症患者稳态时吗氯贝胺（MCB）药代动力学（PK）和代谢的影响。
21例复发性内源性抑郁症住院患者以非随机方式接受MCB（150 mg，每日3次），单独用药或与VPA（500 mg，每日2次）或CBZ（200 mg，每日2次）联合用药。得出MCB及其两种代谢物Ro 12 - 8095和Ro 12 - 5637的稳态血浆PK参数。每周使用标准抑郁评定量表进行治疗效果的临床评估。
联合给药4周后，CBZ而非VPA使MCB的AUC降低35%[从7.794降至5.038 mg·h·l⁻¹；95%置信区间（CI） - 4.84863， - 0.66194；P = 0.01]，Cmax降低28%（从1.911降至1.383 mg·l⁻¹；95% CI - 0.98197， - 0.07518；P < 0.05），口服清除率增加41%（从0.323升至0.454 l·h⁻¹·kg⁻¹；95% CI 0.00086，0.26171；P < 0.05）。MCB的血药浓度也平均降低了41%（从0.950降至0.559 mg·l⁻¹；95% CI - 0.77479， - 0.03301；P < 0.05）。然而，由于几个可能的原因，该组患者的疗效并不低于对照组。所有研究药物的总体耐受性良好。
VPA对MCB的PK或代谢没有显著影响，而CBZ会时间依赖性地降低MCB的暴露量，可能是通过诱导MCB及其主要血浆代谢物的代谢。观察到的MCB - CBZ PK相互作用的实际临床相关性需要在更全面的研究中进一步评估。
