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Effect of CYP1A2 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers
Author(s) -
Song L.,
Du Q.,
Jiang X.,
Wang L.
Publication year - 2014
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12118
Subject(s) - agomelatine , pharmacokinetics , cmax , single nucleotide polymorphism , genotype , pharmacology , medicine , cyp2d6 , pharmacogenetics , cyp1a2 , polymorphism (computer science) , endocrinology , biology , genetics , cytochrome p450 , metabolism , antidepressant , gene , hippocampus
Summary What is known and objective 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 CYP 1A2. The purpose of this study was to assess the influence of CYP 1A2 single nucleotide polymorphisms ( SNP s, rs762551, rs2069514, rs2472304, rs2470890) on agomelatine pharmacokinetics in the Chinese population. Methods Seventy‐two healthy Chinese male volunteers enrolled in the study received an oral dose of 25 mg of agomelatine after providing written informed consent. CYP 1A2 SNP s 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. Results and discussion 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 AUC 0–7 , AUC 0–∞ and C max 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). What is new and conclusion The rs762551 A, rs2470890 T and rs2472304 A genotype presented a significantly lower level of agomelatine exposure ( AUC , C max ) 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.