头孢拉定在糖尿病和正常大鼠体内药动学比较

摘要

Objective To investigate effects of diabetes mellitus (DM) on pharmacokinetics (PK) of cephradine (CED).Methods DM model was induced by iv.alloxan 60 mg·kg-1.A reversed phase HPLC internal standard method was developed for measurement of CED plasma concentration.After blood collection,rats were sacrificed to collect kidneys for calculating kidney index(KW/BW).DM and normal control (CTL) rats were randomly assigned to receive iv.or ig.CED at a dose of 180 or 90 mg·kg-1.The 3p97 program was used to calculate PK parameters.Results The developed HPLC method was validated to have high specificity,precision,recovery and good storage stability,and met requirements for PK study of CED.The CED in rats of both DM and CTL groups showed the iv.two-compartment PK and ig.one-compartment PK and followed the first-order kinetics.Following iv.dosing,a remarkably decreased t1/2β and MRT,increased CLt were evident in DM group as compared with CTL group (P ＜ 0.05).After ig dosing,a significant decrease in t1/2k and t a remarkable increase in CLt and Cm=were observed for DM group as compared with CTL group (P ＜ 0.05).The DM rats showed a trend of decreased t1/2ka vs CTL rats.There was no significant difference in the oral bioavailability between the two groups (P ＞ 0.05).KW and KW/BW in DM group were increased remarkably compared with CTL group (P ＜ 0.05).Conclusion The DM vs CTL results in faster absorption and elimination of CED in rats,but does not have significantly affect in oral bioavailability.The compensatory hypertrophy and hyperfunction of early-stage diabetic kidneys may constitute one of causes of quick elimination of CED in rats with DM.%目的 观察糖尿病(DM)状态对头孢拉定(CED)药动学(PK)的影响.方法 采用静脉注射四氧嘧啶(60mg·kg-1)建立DM大鼠模型.反相高效液相色谱(RP-HPLC)内标法测定血浆CED浓度.称定大鼠肾脏质量(KW),并计算肾脏指数(肾质量/体质量,KW/BW).静脉注射和灌胃大剂量(180 mg· kg-1)、小剂量(90 mg· kg-) CED后测定血药浓度,3p97程序计算PK参数.结果 所建立的方法特异性、精密度和准确度高,符合PK研究要求.正常对照组(CTL)和DM组大鼠静脉注射CED后血药浓度时程均符合二室模型、线性动力学过程;与CTL组比较,DM组t1/2β、MRT明显缩短,CLt显著增加(P＜0.05).2组大鼠灌胃给予CED后血药浓度时程均符合口服一室模型、线性动力学过程;与CTL组比较,DM组灌胃给予CED后tmax、t1/2k显著缩短(P＜0.05),t1/2ka呈缩短趋势,Cmax、CLt明显增加(P＜0.05).两组CED灌胃给药生物利用度(F)差异无统计学意义.DM组KW和KW/BW较CTL组明显升高(P＜0.05).结论 DM导致静脉注射及灌胃CED后药物在大鼠体内的消除明显加快,灌胃给药吸收亦加快,但对F无显著影响.DM早期肾脏出现代偿性肥大,继而功能亢进,可能是DM大鼠CED消除加快的原因之一.