Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge-Karolinska Institutet, 141 86, Stockholm, Sweden.
Eur J Clin Pharmacol. 2010 May;66(5):465-74. doi: 10.1007/s00228-009-0783-8. Epub 2010 Feb 9.
The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia.
A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine.
In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact.
At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.
在精神分裂症患者中，研究 UGT1A4、CYP1A2 和 MDR1 遗传变异与其他个体因素（如性别、吸烟状态、体重和年龄）对奥氮平血浆水平的影响。
从斯德哥尔摩县的精神病专科门诊共招募了 121 名患者。采用高效液相色谱法测定奥氮平的血浆浓度。通过 PCR-限制性片段长度多态性或小测序进行基因分型，使用群体遗传学专用计算机软件分析单体型。采用多元回归分析方法，研究患者特征和基因型/单体型对奥氮平日剂量校正血浆浓度的综合影响。
除了已知的从末次剂量摄入到采样时间的因素外，结果表明，奥氮平暴露的个体间差异还与以下个体因素有关，按相对影响大小排列为：（1）男性，（2）UGT1A4 142T>G 单核苷酸多态性（SNP）携带者，（3）吸烟。这三个因素分别预测奥氮平日剂量校正血浆浓度降低 35%、25%和 21%。相比之下，年龄、体重和 MDR1 或 CYP1A2 单体型则没有显著影响。
在给药后 12 小时，回归模型预测，与携带 UGT1A4 142T>G SNP 的吸烟男性相比，不携带 UGT1A4 142T>G SNP 的非吸烟女性患者的奥氮平血浆水平要高出 5.1 倍，尽管接受了相同剂量的治疗，但携带 UGT1A4 142T>G SNP 的患者则为杂合子。这些综合的遗传和环境因素是否会影响治疗失败的风险，仍有待确定。
