Stage Claus, Jürgens Gesche, Guski Louise Schow, Thomsen Ragnar, Bjerre Ditte, Ferrero-Miliani Laura, Lyauk Yassine Kamal, Rasmussen Henrik Berg, Dalhoff Kim
Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark.
Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark.
Br J Clin Pharmacol. 2017 Jul;83(7):1506-1514. doi: 10.1111/bcp.13237. Epub 2017 Feb 24.
This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate.
CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity. Plasma concentrations of methylphenidate and its primary metabolites were determined at scheduled time points.
Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml h , range 38.6-93.9) than in the control group (21.4 ng ml h , range 15.7-34.9) (P < 0.0001). Median AUC of d-methylphenidate was significantly larger in the group with four CES1 copies (34.5 ng ml h , range 21.3-62.8) than in the control group (P = 0.01) and the group with three CES1 copies (23.8 ng ml h , range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1.
The 143E allele resulted in an increased AUC, suggesting a significantly decreased CES1 enzyme activity. Surprisingly, this was also the case in subjects with homozygous duplication of CES1, perhaps reflecting an undiscovered mutation affecting the activity of the enzyme.
本研究调查了羧酸酯酶1（CES1）变异，包括单核苷酸多态性（SNP）rs71647871（G143E）和拷贝数变异，对单次口服10毫克哌甲酯药代动力学的影响。
从200名健康的丹麦白种人志愿者中获取CES1基因型。根据基因型，邀请了44名（19名男性和25名女性）参与一项开放的前瞻性试验，该试验涉及六种预定义的基因型：分别为三组，每组有两个、三个和四个CES1拷贝；一组为CES1 143E等位基因携带者；一组为CES1A1c纯合子个体（CES1VAR）；以及一组有三个CES1拷贝的个体，其中重复的CES1A2具有增强的转录活性。在预定时间点测定哌甲酯及其主要代谢物的血浆浓度。
携带143E等位基因的组中d - 哌甲酯的中位曲线下面积（AUC）（53.3 ng·ml⁻¹·h，范围38.6 - 93.9）显著大于对照组（21.4 ng·ml⁻¹·h，范围15.7 - 34.9）（P < 0.0001）。有四个CES1拷贝的组中d - 哌甲酯的中位AUC（34.5 ng·ml⁻¹·h，范围21.3 - 62.8）显著大于对照组（P = 0.01）和有三个CES1拷贝的组（23.8 ng·ml⁻¹·h，范围15.3 - 32.0，P = 0.03）。有两个和三个CES1拷贝的组之间没有差异。
143E等位基因导致AUC增加，表明CES1酶活性显著降低。令人惊讶的是，CES1纯合重复的受试者也是如此，这可能反映了一个未被发现的影响该酶活性的突变。
