Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden.
Pharmacogenomics. 2013 Aug;14(11):1319-36. doi: 10.2217/pgs.13.120.
The pharmacokinetics of the atypical antipsychotic, olanzapine, display large interindividual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need for individualized dosing in order to avoid concentration-dependent adverse effects or therapeutic failure. Genetically determined differences in olanzapine metabolism represent a less studied source of variability in comparison to environmental and physiological factors. In this review, we summarize available in vitro and in vivo data addressing the influence of polymorphisms in drug-metabolizing enzymes on olanzapine serum exposure. The polymorphic CYP2D6 enzyme appears to have no significant influence on olanzapine steady-state serum concentrations. The formation of the various olanzapine metabolites is influenced by polymorphisms in the genes coding for CYP1A2, CYP1A expression regulator AHR, UGT1A4 and UGT2B10, as well as FMO3. An impact on steady-state olanzapine serum concentrations has been suggested for variants of CYP1A2 and UGT1A4, with somewhat conflicting findings. The potential involvement of FMO1 and CYP3A43 in olanzapine disposition has also been suggested but needs future validation.
非典型抗精神病药奥氮平的药代动力学表现出较大的个体间差异，导致在给定剂量下患者之间的药物暴露存在多倍差异。这种差异反过来又需要个体化给药，以避免浓度依赖性不良反应或治疗失败。与环境和生理因素相比，遗传决定的奥氮平代谢差异是一个研究较少的变异性来源。在这篇综述中，我们总结了现有的关于药物代谢酶多态性对奥氮平血清暴露影响的体外和体内数据。多态性 CYP2D6 酶似乎对奥氮平稳态血清浓度没有显著影响。各种奥氮平代谢物的形成受到编码 CYP1A2、CYP1A 表达调节剂 AHR、UGT1A4 和 UGT2B10 以及 FMO3 的基因多态性的影响。CYP1A2 和 UGT1A4 的变体对稳态奥氮平血清浓度有影响，但结果有些相互矛盾。FMO1 和 CYP3A43 也可能参与奥氮平的处置，但需要进一步验证。
