摘要
目的比较巴马小型猪CYP3A29和人CYP3A4稳定表达重组肝癌细胞株微粒体的药物代谢特征,在分子水平为巴马小型猪作为临床前药物代谢实验动物提供科学依据。方法以CYP3A特异性代谢底物硝苯地平、睾酮及其抑制药酮康唑为探针药物,将探针药物与重组CYP3A4、CYP3A29细胞微粒体在优化的微粒体浓度、药物浓度、孵育时间等条件下进行体外孵育,高效液相色谱法检测其药物代谢(抑制)动力学参数,并将二者进行比较分析。结果巴马小型猪CYP3A29与CYP3A4在硝苯地平和睾酮代谢差异无统计学意义(P>0.05)。酮康唑的抑制活性为:当代谢底物为硝苯地平时,酮康唑对CYP3A29和CYP3A4的半数抑制浓度分别为0.090,0.132μmol·L-1(P<0.05);当代谢底物为睾酮时,酮康唑对CYP3A29和CYP3A4的半数抑制浓度分别为0.056,0.032μmol·L-1(P<0.05)。结论重组CYP3A29与CYP3A4细胞微粒体对硝苯地平和睾酮活性差异不显著;酮康唑对重组CYP3A29与CYP3A4细胞微粒体硝苯地平和睾酮代谢活性有差异。
Objective To compare the pharmacokinetic characteristics of microsomes from the recombinant cell lines of HepG2 with CYI^A4 and CYP3A29 in Bama miniature pigs, and provide evidence for clinical animal testing. Methods The probe drugs nifedipine （NF）, testosterone （TST） and ketoconazole （KCZ） were incubated with the recombinant microsomes of HepG2-CYP3A4 and HepG2-CYP3A29 under optimal conditions of concentration and duration. The high performance liquid chromatograph （HPLC） was utilized to detect the metabolites, and characteristics of the two types of microsomes were compared. Results There was no significant difference in the metabolic activities between CYP3A29 and CYP3A4 for both nifedipine and testosterone （P 〉 0. 05 ）. The half inhibitory concentrations of ketoconazole for CYP3A29 and CYP3A4 were 0. 090 and 0. 132 μmol·L-1 （P〈0.05）, respectively, using nifedipine as the metabolism substrate, and were 0. 056 and 0.032 μmol·L-1 （P〈0.05）, respectively, using testosterone as metabolism substrate. Conclusion There is no significant difference between cell microsomes with CYP3A29 and CYP3A4 in metabolizing nifedipine and testosterone, but ketoconazole has significantly different inhibitory activity towards the two types of microsomes.
出处
《医药导报》
CAS
2015年第1期15-21,共7页
Herald of Medicine
