Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants.
Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants.
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DOI：
10.1097/fpc.0b013e328348c76b
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发表时间：
2011-09
影响因子：
2.6
通讯作者：
Lazarus P
中科院分区：
文献类型：
--
作者：
Erickson-Ridout KK;Zhu J;Lazarus P
奥氮平（OLZ）是一种用于治疗精神分裂症、双相情感障碍和难治性抑郁症的抗精神病药物。通过udp -葡萄糖醛酸糖醛酸转移酶（UGT）家族进行的糖醛酸化是OLZ代谢的主要方式，这些酶的多态性可能导致OLZ代谢和治疗反应的个体差异。在筛选过表达单个UGTs的细胞系时，只有UGTs 1A4和2B10表现出抗OLZ的糖醛酸化活性。与野生型UGT1A424Pro/48Leu相比，UGT1A424Pro/48Val突变体olz -10- n -葡萄糖醛酸异构体1形成的Vmax/KM高3.7倍（p<0.0001）， olz -10- n -葡萄糖醛酸异构体2形成的Vmax/KM高4.3倍（p<0.0001）。UGT2B1067Y变体对OLZ没有糖醛酸化活性。在对105例人肝微体（HLM）标本的筛选中，与UGT1A4 (*1/*1)/UGT2B10（*1/*1）基因型的HLM相比，UGT1A4 (*3/*3)/UGT2B10（*1/*1）基因型的HLM中OLZ-10- n -葡糖苷异构体1和OLZ-4 ' - n -葡糖苷形成率分别增加2.1倍（p=0.04）和1.6倍（p=0.0017）， OLZ-10- n -葡糖苷形成率增加2.0倍（p=0.02）。在至少有一个UGT2B10*2等位基因的HLM中，olz -10- n -葡萄糖苷异构体的形成减少了1.9倍（p<0.003）， OLZ-4 ' - n -葡萄糖苷形成减少了2.7倍（p<0.0001）， olz -10- n -葡萄糖苷形成减少了2.1倍（p=0.0002）。在回归分析中，UGT1A4*3 （p<0.02）和UGT2B10*2 （p<0.002）等位基因是所有olz -葡糖苷异构体形成的显著预测因子。这些数据表明，UGT1A4*3和UGT2B10*2等位基因对OLZ代谢的个体间差异有重要影响。
Olanzapine (OLZ) is an antipsychotic used in the treatment of schizophrenia, bipolar disorder, and treatment-resistant depression. Glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes is the major mode of OLZ metabolism and polymorphisms in these enzymes could contribute to inter-individual variability in OLZ metabolism and therapeutic response. In a screening of cell lines over-expressing individual UGTs, only UGTs 1A4 and 2B10 exhibited glucuronidation activity against OLZ. The UGT1A424Pro/48Val variant exhibited a 3.7-fold (p<0.0001) higher Vmax/KM for formation of the OLZ-10-N-glucuronide isomer 1 and a 4.3-fold (p<0.0001) higher Vmax/KM for formation of the OLZ-10-N-glucuronide isomer 2 than wild-type UGT1A424Pro/48Leu. The UGT2B1067Y variant exhibited no glucuronidation activity against OLZ. In a screening of 105 human liver microsomal (HLM) specimens, there was a 2.1- (p=0.04) and 1.6- (p=0.0017) fold increase in the rate of OLZ-10-N-glucuronide isomer 1 and OLZ-4’-N-glucuronide formation, and a 2.0-fold (p=0.02) increase in overall OLZ glucuronidation formation, in HLM with the UGT1A4 (*3/*3)/UGT2B10 (*1/*1) genotype compared to HLM with the UGT1A4 (*1/*1)/UGT2B10 (*1/*1) genotype. There was a 1.9-fold (p<0.003) decrease in formation of both isomers of the OLZ-10-N-glucuronide, a 2.7-fold (p<0.0001) decrease in OLZ-4’-N-glucuronide formation, and a 2.1-fold (p=0.0002) decrease in overall OLZ-glucuronide formation in HLM with at least one UGT2B10*2 allele. In regression analysis, both the UGT1A4*3 (p<0.02) and UGT2B10*2 (p<0.002) alleles were significant predictors of formation of all OLZ-glucuronide isomers. These data suggest that the UGT1A4*3 and UGT2B10*2 alleles contribute significantly to inter-individual variability in OLZ metabolism.