1-(4-溴苄基)-1-(4-溴苄氧基)脲药代动力学和体外代谢的研究

Pharmacokinetics and metabolism of 1-(4-bromobenzyl)-1-(4-bromobenzyloxy) urea in vitro

目的研究1-(4-溴苄基)-1-(4-溴苄氧基)脲(HY-D11)在大鼠体内药代动力学过程及其在大鼠肝脏中的代谢途径。方法建立HY-D11的UV-HPLC生物样本检测方法,灌胃给予HY-D11 66.7 mg·kg-1后,观察HY-D11在大鼠体内的药代动力学过程。研究CYP1A抑制剂(α-萘黄酮)、CYP2B抑制剂(舍曲林)、CYP2C抑制剂(槲皮素)、CYP2D抑制剂(育亨宾)、CYP2E抑制剂(双硫仑)及CYP3A抑制剂(醋竹桃霉素)对HY-D11在大鼠肝微粒体温孵液中代谢的影响。结果 HY-D11在大鼠体内的药代动力学过程符合二室模型。药代动力学参数t max为(3.67±0.52)h,C max为(1.61±0.13)mg·L-1,t1/2z为(3.41±3.91)h,平均滞留时间MRT0-∞为(7.05±0.29)h。HY-D11在大鼠微粒体温孵液中呈现明显的酶促动力学特征。醋竹桃霉素组与对照组相比,对HY-D11代谢有明显抑制作用(P<0.01);而与对照组相比,萘黄酮组、舍曲林组、槲皮素组、育亨宾组、双硫仑组对HY-D11的代谢均无抑制作用(P>0.05)。结论 HYD11在大鼠体内吸收、代谢速度较快,在大鼠体内代谢可能主要由CYP3A介导。

Objective To investigate the pharmacokinetics of 1 - （4 - bromobenzyl） - 1 - （4 - bromobenzyloxy） urea（ HY - Dll ） in rats and metabolism of HY - D11 in rat liver microsome incubation system. Meth-ods The HPLC analysis method of HY - D11 in biological sample was set up to investigate its pharmacokinetics after an oral dose of 66. 7 mg · kg^-1 in rats. CYP1A inhibitor （ α - naphthoflavone ）, CYP2B inhibitor （ sertraline ）, CYP2C inhibitor （ quercetin ）, CYP2D inhibitor （ yohim-bine）, CYP2E inhibito （disulfiram） and CYP3A inhibitor （ troleandomy-cin） were used to investigate their inhibitory effects on the metabolism of HY-D11. Results A stable and reliable HY-D11 samples detection method was established. The pharmacokinetic profiles of HY - D11 are described by two - compartment model legitimately. The tmax is （3.67 ± 0.52） h, Cmax is （1.61±0.13） mg· L^-1, t1/2z is （3.66 ±0.25） h, MRT0-∞ is （7. 05 ±0. 29） h. The metabolism of HY - D11 in liver mi- crosome incubation solution showed the characteristic of enzyme kinetics. The α - naphthoflavone, sertraline, quercetin, yohimbine, and disul- firam did not have effect on HY - D11 metabolism in liver microsome in- cubation solution （P 〉 0. 05）. The troleandomycin reduced HY-D11 metabolism in liver microsome incubation solution（P 〈0. 05）. Conclusion The absorption and metabolism of HY - D11 are very rapid. The metabolism of HY- D11l in rats may be mediated by CYP3A.