Song L, Du Q, Jiang X, Wang L
Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
J Clin Pharm Ther. 2014 Apr;39(2):204-9. doi: 10.1111/jcpt.12118. Epub 2013 Dec 27.
Agomelatine is a melatonin (MT) analogue with agonistic properties and has been proven to be effective for various types of depressive symptoms. Following oral administration, agomelatine is primarily metabolized by the hepatic cytochrome P450 isoenzyme CYP1A2. The purpose of this study was to assess the influence of CYP1A2 single nucleotide polymorphisms (SNPs, rs762551, rs2069514, rs2472304, rs2470890) on agomelatine pharmacokinetics in the Chinese population.
Seventy-two healthy Chinese male volunteers enrolled in the study received an oral dose of 25 mg of agomelatine after providing written informed consent. CYP1A2 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Agomelatine plasma concentrations were determined by high performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetics analyses were evaluated by nonparametric methods.
After a single oral dose of 25 mg agomelatine, no significant differences existed in agomelatine pharmacokinetics between the rs2069514 GG homozygotes (n = 35) and the rs2069514 AG allele (n = 35) in all subjects. The mean agomelatine AUC0-7 , AUC0-∞ and Cmax for the rs762551 CC homozygotes (n = 9), rs2470890 CC homozygotes (n = 54) and rs2472304 GG homozygotes (n = 51) were much higher than the rs762551 AA allele (n = 31), rs2470890 CT allele (n = 17) and rs2472304 AG allele (n = 20) respectively (P < 0.05).
The rs762551 A, rs2470890 T and rs2472304 A genotype presented a significantly lower level of agomelatine exposure (AUC, Cmax ) compared with the rs762551 C, rs2470890 C and rs2472304 G genotype in Chinese healthy subjects. It suggested that the rs762551, rs2470890 and rs2472304 genetic polymorphism might be associated with the marked interindividual variability of agomelatine, and the pharmacokinetic profile of agomelatine may be different in different races.
阿戈美拉汀是一种具有激动特性的褪黑素（MT）类似物，已被证明对各种类型的抑郁症状有效。口服给药后，阿戈美拉汀主要通过肝细胞色素P450同工酶CYP1A2进行代谢。本研究的目的是评估CYP1A2单核苷酸多态性（SNP，rs762551、rs2069514、rs2472304、rs2470890）对中国人群中阿戈美拉汀药代动力学的影响。
72名参与本研究的健康中国男性志愿者在提供书面知情同意书后，口服25mg阿戈美拉汀。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对CYP1A2 SNP进行基因分型。采用高效液相色谱-串联质谱法测定阿戈美拉汀血浆浓度，并通过非参数方法评估药代动力学分析。
单次口服25mg阿戈美拉汀后，在所有受试者中，rs2069514 GG纯合子（n = 35）和rs2069514 AG等位基因（n = 35）之间的阿戈美拉汀药代动力学无显著差异。rs762551 CC纯合子（n = 9）、rs2470890 CC纯合子（n = 54）和rs2472304 GG纯合子（n = 51）的阿戈美拉汀平均AUC0-7、AUC0-∞和Cmax分别显著高于rs762551 AA等位基因（n = 31）、rs2470890 CT等位基因（n = 17）和rs2472304 AG等位基因（n = 20）（P < 0.05）。
在中国健康受试者中，与rs762551 C、rs2470890 C和rs2472304 G基因型相比，rs762551 A、rs2470890 T和rs2472304 A基因型的阿戈美拉汀暴露水平（AUC、Cmax）显著较低。这表明rs762551、rs2470890和rs2472304基因多态性可能与阿戈美拉汀显著的个体间变异性相关，并且阿戈美拉汀的药代动力学特征在不同种族中可能有所不同。
