健康人UGT1A9基因多态性与麦考酚酸药动学的关系

 目的探讨中国健康人麦考酚酸(MPA)药动学特性与尿苷二磷酸葡醛酸转移酶UGT1A9基因多态性的关系。方法采集20名健康男性单次po 500 mg麦考酚酸酯后48 h内不同时间点的血样。HPLC测定麦考酚酸(MPA)和葡醛酸化麦考酚酸(MPAG)的药物浓度。UGT1A9的基因多态性采用测序法测定,包括-2208,-2152,-2141,-1887,-1818,-665,-440,-331,-275,-109至-98(Tn),-87 11个位点。结果20名受试者中,-2208,-2152,-2141,-665,-275位点未发现突变,-440和-331位点均为纯合突变型,-1887,-1818,-109至-98(Tn)和-87的突变率分别为0.25,0.7,0.75,0.05。统计学检验未发现MPA和MPAG的ρ_max,AUC_0-t以及二者的比值与上述单核苷酸多态性有显著性差异。结论中国人群UGT1A9的基因多态性与白种人存在差异,且未发现UGT1A9的基因多态性与MPA的药动学特征有关。

Relationship Between Polymorphisms of UGT1A9 Gene and Pharmacokinetic Characteristics of Mycophenolate Acid in Chinese Healthy Subjects

OBJECTIVE To investigate the relationship between polymorphisms of UGT1A9 gene and pharmacokinetic(PK) characteristics of mycophenolate acid(MPA) in vivo.METHODS 20 healthy male volunteers were orally taken 500 mg mycophenolate mofetil(MMF).HPLC method was applied to analyze MPA and mycophenolic acid glucuronide(MPAG) concentration.11 single nucleotide polymorphisms(SNP) of UGT1A9 were determined by sequencing,including-2208,-2152,-2141,-1887,-1818,-665,-440,-331,-275,-109 to-98(Tn) and-87.RESULTS In 20 subjects,there were no mutations at positions of-2208,-2152,-2141,-665,-275,whereas there were all homo-mutations at the positions of-440 and-331.The mutation frequency of-1887,-1818,-109 to-98(Tn) and-87 were 0.25,0.7,0.75 and 0.05 respectively. CONCLUSION There are significant differences between Chinese and Caucasians in terms of UGT1A9 polymorphisms and the current study did not show significant relationship between UGT1A9 polymorphisms and MPA PK profile.