外源性磷酸肌酸在大鼠体内的药代动力学和代谢处置

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, t_1/2β为22.5～23.3 min, V_d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t_max为20 min, t_{1/2k (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t_{1/2k (m)}为56.0～57.7 min, t_max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t_max为68～83 min, t_1/2k为49～52 min; 静注PCr后RBC中未测出PCr, 但测出Cr, 其t_max为120 min, t_{1/2k (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。

Pharmacokinetics and metabolic disposition of exogenous phosphocreatine in rats

This article is report the study of the pharmacokinetics and metabolic disposition of exogenous phosphocreatine (PCr) in rats by means of an ion-pair HPLC-UV assay.  PCr and its metabolite creatine (Cr) and related-ATP in rat plasma and red blood cell (RBC) were simultaneously determined.  A blank plasma and RBC were initially run for baseline subtraction.  Plasma and RBC samples were deproteinized with 6% PCA prior to HPLC.  Following iv administration of PCr 500 mg·kg⁻¹ and 1 000 mg·kg⁻¹ the C-T curve could  be described by the two-compartment model with t_1/2β 22.5−23.3 min, V_d 0.956 4−0.978 6 L·kg⁻¹, CL 0.029 L·kg⁻¹·min⁻¹.  The Cr as PCr degraded product appeared as early as 2 min post iv dosing with t_max 20 min, t_{1/2k (m)} 40.6−42.7 min and f_(m) 60%−76%.  After po administration of PCr, the parent drug in plasma was undetectable, but the metabolite Cr was detected with t_max 65−95 min, t_{1/2k (m)} 56.0−57.7 min, metabolite-based bioavailability F_(m) 55.02%−62.31%.  PCr iv administration resulted in significant elevation of ATP level in RBC but not in plasma, the related-ATP in RBC was characterized by t_max 68−83 min, t_1/2k 49−52 min.  In RBC no exogenous PCr was found but Cr was detected following iv administration of PCr, with the t_max 120 min and t_{1/2k (m)} 70 min for Cr.  The above results indicate that PCr eliminates and bio-transforms in body very rapidly; K > K_(m) confers ERL, instead of FRL, type upon the metabolic disposition of Cr.  Following po administration of PCr, the degraded product Cr is absorbed but not the parent drug PCr.  The formed Cr can be accounted for by most of iv and po PCr.  Intravenous dosing leads apparently increased and sustained Cr and related-ATP concentration in RBC.