自身免疫病患者乳汁中羟氯喹的浓度及其影响因素分析  

Determination of hydroxychloroquine and its metabolites in the breast milk of patients with autoimmune disease

作　　者：束庆[1] 葛泳含 魏禺 江源[3] 梅洪梁 冯学兵[2] 葛卫红[1] 朱赟[2] Shu Qing;Ge Yonghan;Wei Yu;Jiang Yuan;Mei Hongliang;Feng Xuebing;Ge Weihong;Zhu Yun(Department of Pharmacy,Affiliated Drum Tower Hospital of Nanjing University Medical School,Jiangsu 210008,China;Department of Rheumatology and Immunology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Jiangsu 210008,China;Department of Obstetrics and Gynecology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Jiangsu 210008,China)

机构地区：[1]南京大学医学院附属鼓楼医院药学部,210008 [2]南京大学医学院附属鼓楼医院风湿免疫科,210008 [3]南京大学医学院附属鼓楼医院妇产科,210008

出　　处：《中华风湿病学杂志》2020年第6期369-376,共8页Chinese Journal of Rheumatology

基　　金：家自然科学基金(81603087);江苏省医学创新团队项目(CXTDA2017041);江苏省药学会-奥赛康医院药学基金项目(A201704);南京市医学科技发展资金项目(QRX17140,QRX17040);南京鼓楼医院新技术发展基金项目(XJSFZJJ201806)。

摘　　要：目的检测自身免疫病患者乳汁中羟氯喹及其活性代谢物去乙基羟氯喹(DHCQ)的浓度,结合观察随访,评价哺乳期服用羟氯喹对婴儿的安全性,并探讨导致患者乳汁中药物浓度个体差异的因素。方法纳入服用羟氯喹至少6个月且处于哺乳期的自身免疫病患者,通过建立一种新的高效液相色谱法来检测患者服药前(0 h)、服药后2、4、6 h乳汁样本和服药后6 h全血中羟氯喹及DHCQ的浓度。其次通过测定患者与羟氯喹代谢相关的细胞色素酶P450(CYP)的CYP3A4*1G(rs2242480)、CYP3A5*3(rs776746)、CYP2D6*10(rs1065852、rs1135840)的基因型,分析代谢酶基因多态性与患者乳汁中药物浓度个体差异的相关性。随访哺乳患者的婴儿的视力、听力及一般生长状况。统计学方法采用单因素方差分析、独立样本t检验、χ2分析及Pearson相关性分析。结果共纳入15例患者,服用200 mg/d的患者羟氯喹和DHCQ的平均浓度分别为(520±261)ng/ml、(177±112)ng/ml;服用400 mg/d的患者羟氯喹和DHCQ的平均浓度分别为(1036±374)ng/ml、(397±271)ng/ml。全血中羟氯喹平均浓度为(661±308)ng/ml,DHCQ平均浓度为(267±73)ng/ml。其中,4例患者服药后2 h乳汁中羟氯喹及DHCQ浓度达到高峰,11例于服药后4 h乳汁中羟氯喹及DHCQ浓度达到高峰。不同CYP基因型与患者乳汁中药物浓度和达峰时间的个体差异未见相关性。随访服用含有羟氯喹的乳汁5~10个月的婴儿的听力、视力、一般生长状况均无异常。结论乳汁羟氯喹、DHCQ浓度与患者服药剂量呈正相关,乳汁中羟氯喹、DHCQ浓度在服药后4 h达到高峰,服药6 h后乳汁中羟氯喹、DHCQ的浓度和血液浓度相近。建议哺乳期服用羟氯喹的患者可于服药4 h后进行哺乳,减少婴儿通过乳汁摄取的羟氯喹及其活性代谢物。但是,羟氯喹对于婴儿的安全性和CYP基因多态性对于乳汁浓度的影响未来仍需扩大样本和进行长期随访来进一步验Objective To determine the concentration of hydroxychloroquine(HCQ)and its active metabolite deethylhydroxychloroquine(DHCQ)in breast milk of lactating patients with autoimmune disease.To observe the safety of hydroxychloroquine in lactation period,and to explore the factors that may affect HCQ and DHCQ concentration in the milk.Methods Lactating patients with autoimmune disease who have taken HCQ for at least 6 months were included in our study.A new high performance liquid chromatography(HPLC)method was established to detect HCQ and DHCQ levels in breast milk.Milk samples were collected at different time points:before taking the drug(0 hours),and 2 hours,4 hours,6 hours after taking the drug.In addition,the genotype of cytochrome CYP3A4*1G,CYP3A5*3 and CYP2D6*10 which were related to HCQ metabolism were tested by dideoxy chain termination method.Visual acuity,hearing and growth status of the patients'infants were followed up on a regular basis.T-test,one-way ANOVA and Pearson's test were used for data analysis.Results In 15 patients,the average concentration of HCQ and DHCQ in the milk of patients taking 200 mg/d were(520±261)ng/ml and(177±112)ng/ml,respectively.While the average concentration of HCQ and DHCQ in the milk of patients taking 400 mg/d were(1036±374)ng/ml and(397±271)ng/ml,respectively.The peak of HCQ level for 11 patients was at 4 hour after taking the drug,while the others'were at 2 hour.The breast-fed infants did not show any abnormal symptoms of hearing,vision and growth.However,cytochrome gene polymorphism did not affect the peak of HCQ and DHCQ.Conclusion The concentration of HCQ and DHCQ in breast milk is positively correlated to the dosage.The peak level of HCQ milk is 4 hours after taking the drug.The levels of HCQ and DHCQ at 6 hours are similar as those in the whole blood.It is suggested that patients who take HCQ can feed 4 hours after taking the drug to reduce the HCQ and its active metabolites being absorbed by infants.However,the impact of HCQ on infant safety and gene polymorphi

关 键 词：羟氯喹 自身免疫疾病 乳汁 全血药物浓度 去乙基羟氯喹 肝药酶基因多态性 

分 类 号：R593.2[医药卫生—内科学]