【摘要】 目的 研究不同剂量丙磺舒(PBC)对头孢克罗(CCL)药动学的影响，探讨两药单次联用时最佳比例。方法 家兔42只，随机分成7组：Ⅰ组单用CCL 50mg/kg；Ⅱ～Ⅵ组CCL 50mg/kg分别联用PBC 50、100、200、300及400mg/kg；Ⅶ组CCL 25mg/kg联用PBC 100mg/kg。两药均灌胃给予。给药后不同时间点取血,HPLC法测定CCL血药浓度。结果 ①在实验剂量范围内，随着PBC剂量增大，CCL的t1/2ke、t1/2ka、tmax、MRT持续延长，PBC剂量较大时各值较CCL单用时有显著差异(P<0.05及P<0.01)；②在PBC为50～200mg/kg范围内，CCL的cmax、AUC持续增高，CL/F持续降低；当PBC高于200mg/kg时，CCL的cmax反降低，而AUC、CL/F稳定在PBC 200mg/kg水平；③CCL 25mg/kg联用PBC 100mg/kg时，CCL血药浓度可达到CCL 50mg/kg单用时水平。结论 ①联用PBC可显著改变CCL的药动学特性，变化趋势与PBC剂量密切相关；②适量联用PBC，可提高CCL的cmax，延长其t1/2；当PBC联用剂量过大，cmax反而降低，可能因为PBC干扰了CCL的吸收；③本实验中CCL与PBC单次联用剂量比以1∶4为宜。
【关键词】 丙磺舒 头孢克罗 药动学 HPLC 家兔
Effects of probenecid on the pharmacokinetics of cefaclor in rabbits
ABSTRACT Objective To investigate effects of probenecid (PBC) at different doses on the pharmacokinetics of cefaclor (CCL) and to explore a suitable proportion of their single coadministration. Methods Fortytwo rabbits were randomly divided into 7 groups: CCL 50 mg/kg, alone CCL 50 mg/kg combined with PBC 50 mg/kg, CCL 50 mg/kg combined with PBC 100 mg/kg, CCL 50 mg/kg combined with PBC 200 mg/kg, CCL 50 mg/kg combined with PBC 300 mg/kg, CCL 50 mg/kg combined with PBC 400 mg/kg, CCL 25 mg/kg combined with PBC 100 mg/kg. Both drugs were given through intragastric administration, but CCL was 30 min later than PBC. Blood samples were drawn from thigh vein at 0, 10, 20, 30, 45, 60, 90, 120, 180, 240 and 360 min after CCL administration. Plasma CCL concentration were determined by HPLC method, and the pharmacokinetic parameters were calculated with 3P87 programme. Results ① Concentrationtime course of CCL in plasma fitted a onecompartment open model. ② Within the range of experimental dosages, continuous prolongation in t1/2ke and MRT were observed, which showed a dosedependent relationship with the increase dosage of PBC the values of r were 0.9876 and 0.9973, respectively; t1/2 and tmax prolong when higher doses of PBC ( ) were used and showed significant difference compared with I (CCL 50 mg/kg administration alone) (P<0.05 and P<0.01, respectively). cmax and AUC of CCL increased and CL/F decreased continuously, and the standard curve was linear over the concentration range of 50 to 200 mg/kg of PBC (the values of r 0.9918, 9.9952 and 0.9036, respectively). Honever, cmax decreased (r=0.9866) when doses of PBC were higher than 200 mg/kg, and AUC and CL/F of CCL maintained at the levels of those with PBC 200 1CCL was able to reach an ideal level in plasma when CCL 50 mg/kg was coadministrated with PBC 200 mg/kg. With such a proportion, when half the dosage of CCL combined PBC were used, a similar plasma level of CCL could be produced as CCL 50 mg/kg used alone. Conclusions ① Coadministration with PBC cluld markedly alter the pharmacokinetics of CCL, and the effects on every parameter were closely dependent on doses of PBC. ② Values of cmax, AUC and t1/2ke of CCL increase or prolong by coadministrating with proper dosage of PBC, and the efficacy of CCL can be increased; but overdose of PBC results in the decrease in cmax of CCL, and it might be for PBC interfere with the absorption of CCL through gastrointestinal tract. ③ The result of this study suggests that the proportion of CCL combined with PBC in single close is 1 to 4.
KEY WORDS Probenecid; Cefaclor; Pharmacokinetics; HPLC; Rabbit
丙磺舒(probenecid，PBC)为一促尿酸排泄药，是许多药物经肾小管主动排泌的抑制剂［1］。自Beyer发现PBC可提高青霉素的血药水平之后，相继发现丙磺舒对多种β内酰胺类抗生素的药动学均有影响，如延缓后者的排泄，提高血药浓度，延长半衰期等。临床上PBC可作为某些β内酰胺类抗生素的辅助剂，以提高抗生素的血药浓度，延长其抗菌作用时间［2，3］。头孢克罗(cefaclor，CCL)系第二代头孢菌素，主要以原形经肾小管排泌清除［4］。本研究以家兔为实验对象，观察不同剂量PBC对CCL的药动学影响，并探索两者单次联用时的最佳比例。
1 材料与方法
1.1 药品与试剂
CCL标准品(中国药品生物制品检定所提供)，CCL胶囊(每粒250mg，山东淄博新达制药有限公司，批号010807)，PBC片(每片250mg，上海集成药厂，批号20000803)，乙腈、高氯酸、冰乙酸、三乙胺均为分析纯。
1.2 动物
健康青紫兰家兔，体重(2.2±0.3)kg，兔龄6个月(皖南医学院实验动物中心提供)，实验前12h禁食、不禁水，实验后4h内禁食、禁水。室温：(20±3)℃，湿度：(65±5)%。
1.3 仪器与色谱条件
美国惠普公司HP1100高效液相色谱仪(G1312A二元泵、G1316A柱温箱、G1314A紫外检测器)，预柱：Zobax ODS 4.6mm×12.5mm，分析柱：Hypersil ODS 4mm×125mm， μm。流动相：甲醇∶水∶冰乙酸(20∶80∶0.4)。流速：1.0ml/min。紫外检测波长：264nm。柱温：30℃。
1.4 样品处理
精确量取兔血浆0.2ml，加入6%(V/V)高氯酸0.20ml，旋涡混匀1min，3000r/min离心10min，取上清液20μl进样。
1.5 标准曲线绘制
制作精确称取CCL标准品，以兔空白血浆配制成0、0.25、0.5、1，5、10、20、50和100mg/L的标准系列，按1.4项方法处理后进样。以血药浓度(C)对峰面积(A)绘制标准曲线。
1.6 实验步骤
家兔42只，随机分7组，每组雌、雄各半。Ⅰ～Ⅶ组PBC分别按0(等量0.5%的纤维素溶液)、50、100、200、300、400和100mg/kg溶入20ml 0.5%的纤维素溶液后灌胃给药，0.5h后均以CCL 50mg/kg(Ⅶ组CCL为25mg/kg)灌胃给药；各兔于灌胃结束后0、10、20、30、45、60、90、120、180、240和360min分别由股静脉取血0.8ml，即刻离心分离血浆，按1.4项方法测定CCL的血药浓度。
1.8 数据处理
DAS软件计算药动学参数［5］，数据以(±s)表示，组间比较用t检验。
2 结果
2.1 标准曲线和色谱行为
2.1.1 标准曲线 本法检测CCL的线性范围为0.25～100mg/L，回归方程：
A=9.306C+2.509 r=0.99998(n=5)
最低检出浓度为0.1mg/L。
2.1.2 色谱行为 CCL与血浆组分分离良好，保留时间约4.5min。PBC对色谱无干扰。
2.2 血药浓度
见Tab.1，血药浓度时间曲线见Fig.1。
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