羟氯喹亚麻酸酯在大鼠体内的药代动力学和组织分布的研究

Pharmacokinetics and tissue distribution of acid ester of hydroxychloroquine and linolenic acid in rats

目的研究羟氯喹亚麻酸酯(AHQ)在大鼠体内的药代动力学及组织分布特征。方法色谱柱:ASB C18(50 mm×2. 1 mm,3μm),流动相为乙腈-0. 5%甲酸水溶液=55∶45,流速:0. 4 m L·min^(-1),进样量:50μL。12只SD大鼠单次静脉注射或灌胃给予羟氯喹亚麻酸酯10 mg·kg^(-1),用沉淀蛋白-LC/MS/MS测定羟氯喹亚麻酸酯及主要代谢产物(羟氯喹)在大鼠血浆和组织中的浓度,用Win Nonlin 6. 2软件计算药代动力学参数。结果羟氯喹亚麻酸酯在大鼠体内吸收迅速,在体内的主要药代动力学参数:tmax为(1. 1±0. 2) h,Cmax为(1055. 0±251. 2) ng·m L^(-1);与相同剂量静脉注射后的达峰浓度相比,羟氯喹亚麻酸酯在大鼠体内的绝对生物利用度为30%,在大鼠体内迅速代谢消除,其t1/2为(2. 7±0. 3) h,羟氯喹的转化率为50%。不同组织中羟氯喹亚麻酸酯/羟氯喹的分布由大到小的顺序为肝>肾>小肠>肺>心脏>胃>脾>脑。结论羟氯喹亚麻酸酯经灌胃后,吸收快、消除半衰期短和组织分布广泛,且在不同组织中均能够良好的转化为羟氯喹。

Objective To study the pharmacokinetics and tissue distribution characteristics of acid ester of hydroxychloroquine and linolenic acid( AHQ) in rats.Methods At the chromatographic column ASB C18( 50 mm × 2.1 mm,3 μm) with the mobile phase is acetonitrile-0.5%formate aqueous solution = 55∶45 at a flow rate of 0.4 m L·min^-1.The injection volume was 50 μL.The protein-precipitation-LC/MS/MS method was used to determine the concentration of AHQ and hydroxychloroquine( HCQ) in plasma and tissues after single intravenous or intragastric administration of AHQ( 10 mg·kg^-1) in 12 SD rats.The pharmacokinetic parameters was calculated by Win Nonlin 6.2 software.Results AHQ was absorbed rapidly after single intragastric administration.The main pharmacokinetic parameters of AHQ were as follows: tmaxwas( 1.1 ±0.2) h;Cmaxwas( 1055.0±251.2) ng·m L^-1;t1/2 was( 2.7±0.3) h.The absolute bioavailabity of AHQ was 30% in rats.The main metabolite of AHQ was HCQ,the conversion rate was 50%.Furthermore,the highest concentration of AHQ/HCQ was in liver,followed by kidney and small intestine,and very low in heart,stomach,spleen and brain.Conclusion AHQ is a novel pre-drug with short half-life and extensive distribution,it can rapidly convert into HCQ.