摘要
本文对使用稳定同位素标记药物进行药代动力学/生物等效性研究的方法进行了探索,首次评价了磷酸左奥硝唑酯二钠在食蟹猴体内的药代动力学参数,并证实了磷酸左奥硝唑酯二钠的前药特征。将稳定同位素^(15)N标记后的磷酸左奥硝唑酯二钠和左旋奥硝唑(参比药物)以等摩尔量混合后经同一给药途径同时给予动物,使用液相色谱串联质谱法(LC-MS/MS)检测给药前和给药后不同时间的血药浓度,计算药代动力学参数,并对^(15)N-磷酸左奥硝唑酯二钠进入体内生成的^(15)N-左旋奥硝唑与左旋奥硝唑的机体暴露量进行等效性分析。此外,也对^(15)N-磷酸左奥硝唑酯二钠和磷酸左奥硝唑酯二钠药代动力学行为的一致性进行了验证。研究结果表明,磷酸左奥硝唑酯二钠给药后迅速代谢为左旋奥硝唑,其主要代谢产物左旋奥硝唑的药代动力学特征与等摩尔给药的左奥硝唑基本一致,机体暴露也随着给药剂量的增加而成比例地增加。本研究所用的生物等效性研究方法不同于传统的两周期交叉设计,可避免给药周期、个体内变异、给药顺序等因素对生物等效性结果的影响。本研究所得结果已成功支持了该药物在人体中使用同样思路进行比较药代动力学/生物等效性研究。
This study was carried out to investigate the pharmacokinetics/bioequivalence of levornidazole disodium phosphate by using stable isotope labeled drug,evaluated the pharmacokinetic profile and confirmed the prodrug characteristics of levornidazole disodium phosphate in monkey.Levornidazole（Drug A）and stable isotope ^15N labeled levornidazole disodium phosphate（Drug B）were mixed with equal mole amount（experiment I）;stable isotope ^15N labeled levornidazole disodium phosphate（Drug B）and levornidazole disodium phosphate（Drug C）were mixed with equal mole amount,respectively.After giving the mixed drugs to the monkey,the concentration of ^15N-levornidazole disodium phosphate,levornidazole disodium phosphate,^15N-levornidazole and levornidazole in plasma samples of pre-dosing and 24 h after administration were analyzed by a liquid chromatography-mass spectrometry/mass spectrometry（LC-MS/MS）method.Pharmacokinetic calculations were performed through non-compartmental analysis using Win Nonlin software.Two-sided 90%confidence intervals（CI）were used to evaluate the bioequivalence of two drugs.The results showed that levornidazole disodium phosphate was metabolized to levornidazole rapidly after administration,the body exposure were increased with the dosage.The method of bioequivalence used in this study was different from the traditional two periods,crossover design.By using the method of this study,the effects of administration period,intraindividual variability,and sequence of administration on bioequivalence were avoided.The results of this study had successfully supported the pharmacokinetic and bioequivalence study of this drug in human using the same approach.
出处
《药学学报》
CAS
CSCD
北大核心
2018年第1期90-96,共7页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(81403015)
国家“十三五”重大新药创制专项资助项目(2017ZX09304031-001)
