头孢三嗪噻肟与头孢氨噻肟在中国健康成人中多次给药的药代动力学比较

MULTIPLE-DOSE PHARMACOKINETICS OF CEFTRIAXONE AND CEFOTAXIME IN CHINESE HEALTHY ADULTS

本项研究目的是比较头孢土嗪噻肟(ceftriaxone,CTRX)临床常用的几种每日单次给药方案与作者建议的每日2次给药方案进行比较,并在研究比较的基础上提出2种治疗方案供临床参考。多次给药的血药浓度可以在单次给药的药代动力学参数的基础上,用电脑进行计算,并可根据药物在体内的时间过程与血浆浓度、治疗反应及其他因素(消除半衰期、血浆蛋白结合率等)之间的相互关系对适宜的剂量方案进行评价。按照我们先前对CTRX与CTX所进行的单次给药药代动力学比较研究,用其中静脉给药的药代动力学参数。利用IBM PC/AT电脑,估算出10种多次给药的给药方案。所用程序由中国科学院数学研究所提供。从10种方案中选出一种比较合理的方案B-1,在6名中国男性成人志愿者中进行多次给药药代动力学研究。研究结果表明:在为期5天的疗程内,静脉给药10次,所得药代动力学参数与电脑估算结果非常相似。实测与估算的药代动力学参数表明:CTRX多次给药后各次血药浓度均明显高于CTX,与单次给药药代动力学研究结果相符。作者建议的二种治疗方案为: B-1 用于中度感染:最初48h,1g q12h×2d。第3—7天,0.5g q12h×5d。B-2 用于重度感染:最初48h,每12h给药1次,第1次2g,第2次1g。第3—7天,每日2次,每次1g,间隔12h。

The pharmacokinetics of ceftriaxone and cefotaxime werestudied in ten healthy adults. Each dose of 1 g was administered intra-musctilarly or intravenously in a crossover design study with an intervalof two weeks. Plasma and urine concentrations of antibiotics were mea-sured by bioassay method. An international standard strain K1. Pneu-moniae 1098 was used as assay strain and the Oxoid iso-sensitest mediawere used as assay media .Concentration-time curves were charaterized bylinear one-, and two-compartment open model for intramusclar and andintravenous administrations respectively. The pharmacokinetic parame-ters were obtained by using IBM PC/AT MCPKP Program. The resultsshowed that data obtained from Chinese volunteers were similar to thosereported in literature. After 1 g iv dosing, the initial serum level ofcefotaxime was only about half of that of ceftriaxone. Cmax of ceftiaxoneand cefotaxime after 1 g im injection were 91. 17±16. 04 and 25 .09±8. 22mg/l respectively. Ceftriaxone showed exceptionally long eliminationhalf-life, t_(1/2)β of ceftriaxone after im and iv injection were 7. 07±1 .84 and 7.83±2.56 h respectively, Which were 5.9 and 7.6 times of thoseof cefotaxime. AUCs of ceftriaxone and cefotaxime after im and ivinjection were 1173±266, 1193±350 and 64.06±12.58, 67.91±12.89 mg.h/lrespectively. Both drugs showed good biovailability. F values of ceftria-xone and cefotaxime were 95 .97% and 91 .07% respectively. The total bodyclearance, renal clearance and apparent volume of distribution (Vd) ofceftriaxone were much lower that of cefotaxime. It was considered thatthe low clearance of ceftriaxone was due to the high protein binding rateresulting in persistenaly high steady-state of plasma concentration,long half life, high value of AUC and low renal clearance.