Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark.
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.
Basic Clin Pharmacol Toxicol. 2019 Jul;125(1):54-61. doi: 10.1111/bcpt.13212. Epub 2019 Apr 24.
The present clinical trial investigated the impact of selected SNPs in CES1 on the metabolic activity of the enzyme. For this purpose, we used methylphenidate (MPH) as a pharmacological probe and the d-RA/d-MPH (metabolite/parent drug) ratios as a measure of enzymatic activity. This metabolic ratio (MR) was validated against the AUC ratios (AUC /AUC ). CES1 SNPs from 120 volunteers were identified, and 12 SNPs fulfilling predefined inclusion criteria were analysed separately, comparing the effect of each genotype on the metabolic ratios. The SNP criteria were as follows: presence of Hardy-Weinberg equilibrium, a minor allele frequency ≥ 0.01 and a clearly interpretable sequencing result in at least 30% of the individuals. Each participant ingested 10 mg of racemic methylphenidate, and blood samples were drawn prior to and 3 hours after drug administration. The SNP analysis confirmed the considerable impact of rs71647871 (G143E) in exon 4 on drug metabolism. In addition, three volunteers with markedly lower median MR, indicating decreased CES1 activity, harboured the same combination of three SNPs in intron 5. The median MR for these SNPs was 8.2 for the minor allele compared to 16.4 for the major alleles (P = 0.04). Hence, one of these or the combination of these SNPs could be of clinical significance considering that the median MR of the G143E group was 5.4. The precise genetic relationship of this finding is currently unknown, as is the clinical significance.
本临床试验研究了 CES1 中选定的 SNP 对酶代谢活性的影响。为此，我们使用哌醋甲酯（MPH）作为药理学探针，并用 d-RA/d-MPH（代谢物/母体药物）比值作为酶活性的衡量标准。该代谢比值（MR）与 AUC 比值（AUC /AUC ）进行了验证。从 120 名志愿者中鉴定出 CES1 SNP，并分别分析了符合预定义纳入标准的 12 个 SNP，比较了每种基因型对代谢比值的影响。SNP 标准如下：存在 Hardy-Weinberg 平衡、次要等位基因频率≥0.01 以及在至少 30%的个体中具有可解释的测序结果。每位参与者服用 10mg 外消旋哌醋甲酯，在给药前和给药后 3 小时抽取血样。SNP 分析证实了外显子 4 中的 rs71647871（G143E）对药物代谢的显著影响。此外，有 3 名志愿者的中位 MR 明显较低，表明 CES1 活性降低，他们在 5 号内含子中携带相同的三个 SNP 组合。这些 SNP 的中位 MR 为 8.2 （次要等位基因），而主要等位基因的中位 MR 为 16.4（P=0.04）。因此，考虑到 G143E 组的中位 MR 为 5.4，这些 SNP 中的一个或其组合可能具有临床意义。目前尚不清楚这一发现的确切遗传关系及其临床意义。
