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应用离子对反相高效液相色谱法(IP-RPHPLC)同时测定大鼠血浆和红细胞(RBC)中磷酸肌酸(PCr)及其代谢物肌酸(Cr)以及相关ATP的浓度,从而研究外源性PCr在大鼠血浆及RBC的药代动力学和代谢处置。选用Kromasil-C18色谱柱,四丁基硫酸氢铵为反离子,以基线扣除法计算外源性PCr、Cr和相关ATP。样品经6%PCA预处理后采用IP-RPHPLC法分析。大鼠静注PCr 500和1 000 mg.kg-1后血浆中PCr的消除符合二室模型,t1/2β为22.5～23.3 min,Vd为0.956 4～0.978 6 L.kg-1,CL为0.029 L.kg·1.min-1;静注PCr后血浆中迅即测出其降解产物Cr,其tmax为20 min,t1/2k(m)为40.6～42.7 min,f(m)为60%～76%;大鼠灌胃PCr后血浆中未测出PCr,但测出Cr,Cr的t1/2k(m)为56.0～57.7 min,tmax为65～95 min。基于代谢物计算得到的生物利用度F(m)为55.02%～62.31%。静注和口服PCr后血浆中均未测出ATP,但PCr静注后RBC中测出相关ATP。其tmax为68～83 min,t1/2k为49～52 min;静注PCr后RBC中未测出PCr,但测出Cr,其tmax为120 min,t1/2k(m)为70 min。由上可见,PCr静注后消除快速,并多半转化为Cr,生成的Cr清除较慢,其处置属于消除速率限速型(ERL)。口服PCr后主要以降解产物Cr形式吸收,静注PCr后RBC中Cr和ATP水平明显升高,并较长时间维持于较高水平。
The plasma creatine (PCr) and its metabolite creatine (Cr) and related ATP concentrations in rat plasma and erythrocyte (RBC) were simultaneously determined by ion-pair reversed-phase high performance liquid chromatography (IP-RPHPLC) Pharmacokinetics and Metabolism of Derived PCr in Rat Plasma and RBC. Kromasil-C18 column and tetrabutylammonium hydrogen sulfate as counterion were used to calculate exogenous PCr, Cr and related ATP by baseline subtraction. Samples were pretreated with 6% PCA and analyzed by IP-RPHPLC. PCr 500 and 1 000 mg.kg-1 in rats after plasma PCr elimination consistent with two-compartment model, t1 / 2β was 22.5 ~ 23.3 min, Vd 0.956 4 ~ 0.978 6 L.kg-1, CL 0.029 L.kg · 1.min-1; PCr immediately after intravenous injection of its degradation products measured in the plasma Cr, the tmax of 20 min, t1 / 2k (m) 40.6 ~ 42.7 min, f (m) 76%. PCr was not detected in plasma of rats after intragastric administration of PCr, but the t1 / 2k (m) of Cr and Cr were 56.0-57.7 min and tmax was 65-95 min. The calculated bioavailability F (m) based on metabolites was 55.02% -62.31%. ATP was not detected in plasma following intravenous and oral PCr administration, but ATP was detected in RBC after intravenous infusion of PCr. The tmax was 68-83 min and t1 / 2k was 49-52 min. PCr was not detected in the RBC after intravenous injection of PCr, but Cr was measured with a tmax of 120 min and a t1 / 2k (m) of 70 min. It can be seen from the above that PCr is rapidly eliminated after intravenous injection and mostly converted to Cr, resulting in a slower removal of Cr and a disposal rate of ERL. After oral administration of PCr, it was mainly absorbed in the form of degradation product Cr. The level of Cr and ATP in RBC increased significantly after PCr intravenous injection and maintained at a relatively high level for a long time.