丙磺舒对头孢克罗肠道吸收的影响

摘要/Abstract

摘要： 目的研究不同剂量丙磺舒联用对头孢克罗肠道吸收的影响及其可能机制。方法 (1) 药代动力学试验:头孢克罗(100 mg/kg) 对大鼠静脉给药, 分别与不同剂量丙磺舒(0 、300 、600 、900 mg/kg) 联用, HPLC 监测用药后不同时间的血药浓度, DAS 软件计算头孢克罗的药代动力学参数。(2) 肠道吸收试验:头孢克罗(30μg/mL) 分别与不同剂量丙磺舒(0 、90 、180 、270μg/mL) 联用, 对大鼠在体肠回流给药, 给药后不同时间采样,HPLC 测定灌流液中头孢克罗浓度的经时变化。结果 (1) 头孢克罗静脉给药的血药浓度-时间曲线呈二室开放模型;在试验剂量范围内, 随丙磺舒联用剂量增大, 头孢克罗的血药浓度呈剂量依赖性增高;AUC 与丙磺舒联用剂量呈正相关(r=0.997), 而Cl 、Vd 及V1 与丙磺舒联用剂量呈负相关(r=-0.837,-0.817 及-0.888)。(2) 大鼠在体肠回流实验表明, 不同剂量丙磺舒联用对头孢克罗肠道吸收影响的程度不同, 当丙磺舒联用剂量达270μg/mL 水平时, 灌流液内头孢克罗的留存率明显增高。结论与适量丙磺舒联用,头孢克罗分布容积及血浆清除率降低, 血药浓度增高;而与大剂量丙磺舒联用则明显延缓或抑制头孢克罗的肠吸收, 使头孢克罗血药浓度降低, 该现象可能与大剂量丙磺舒抑制头孢克罗的肠道吸收有关, 其机制有待进一步阐明。

关键词: 丙磺舒, 头孢克罗, 药动学, 吸收, HPLC

Abstract: AIM: To investigate the effect of probenecid on intestinal absorption of cefaclor and possible mechanisms involved.METHODS: Pharmacokinetic experiments:cefaclor (100 mg/kg, i.v.) was given alone or in the presence of probenecid (300, 600 and 900 mg/kg, i.g.) to rats.Plasma concentrations of cefaclor were determined by HPLC and the corresponding parameters were calculated with DAS software.Intestinal absorption experiment:cefaclor (30μg/mL) was co-administered with different dosages of probenecid (0, 90, 180 and 270μg/mL) using an in vivo perfusion technique in rats.The effect of probenecid on intestinal absorption of cefaclor was investigated by the way of perfusion in the intestine from proximal 2 cm duodenum distal to 10 cm from ligament of Treitz.RESULTS: The plasma cefaclor concentration-time curves after i.v.administration were fitted to a two-compartment open model.Within the range of experimental dosages, the plasma concentrations of cefaclor increased in a dose-proportional manner with probenecid dosage increasing.AUC of cefaclor was positively correlated with probenecid dosage(r=0.997).In contrast, Cl, Vd and V1 of cefaclor were negatively correlated with probenecid dosage(r=-0.837,-0.817 and-0.888, respectively).Meanwhile, the mean residual percentage of cefaclor in perfusate increased dramatically only when probenecid dosage increased to 270μg/mL.CONCLUSION: Proper dosage of probenecid co-administration may result in a decrease in Vd and Cl of cefaclor and an increase in plasma cefaclor concentration. While high dosage of probenecid may decrease the cefaclor plasma concentration.The mechanism underlying may be related to the hindrance effect on cefaclor intestinal absorption with high dosage of pobenecid co-administration, mechanism in detail remains to be clarified.

Key words: probenecid, cefaclor, pharmacokinetics, absorption, HPLC

中图分类号:

R969.1

张秀红, 马张庆, 桂常青, 宋建国. 丙磺舒对头孢克罗肠道吸收的影响[J]. 中国临床药理学与治疗学, 2008, 13(12): 1344-1349.

ZHANG Xiu-hong, MA Zhang-qing, GUI Chang-qing, SONG Jian-guo. Effects of probenecid on intestinal absorption of cefaclor in rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(12): 1344-1349.

参考文献

[1] Spina SP, Dillon EC Jr.Effect of chronic probenecid therapy on cefazolin serum concentrations[J].J Ann Pharmacother, 2003, 37(5):621-624.
[2] Garton AM, Rennie RP, Gilpin J, et al.Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels[J].J Antimicrob Chemother, 1997, 40(6): 903-906.
[3] Rao PP, Mopkar O, Desai A.Comparative trial to evaluate the efficacy and tolerability of cefuroxime 250 mg with probenecid with cefuroxime 500 mg in the management of community acquired pheumonia, acute bronchitis and acute exacerbation of chronic bronchitis[J].J IndiaMed Assoc, 2000, 98(10):650-654.
[4] Khamdang S, Takeda M, Babu E, et al.Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics[J].Eur J Pharmacol, 2003, 465(1/2):1-7.
[5] Wang CS, Ma ZQ, Song JG.Effects of probenecid on pharmacokinetics of cefaclor in rabbits[J].Chin J Pharmacol Ther, 2002, 7(2):130-133.
[6] Zhang XH, Ma ZQ, Gui CQ, et al.Effects of probenecid on pharmacokinetics of cefaclor in rats[J].Chin J Pharmacol Ther, 2004, 9(5):523-526.
[7] Saitoh H, Gerard C, Aungst BJ.The secretory intestinal transport of some β-lactam antibiotics and anionic compounds: a mechanism contributing to poor oral absorption [J].Pharmacol Exp Ther, 1996, 278(1):205-211.
[8] Saito H.Molecular and cell biological analyses for intestinal absorption and renal excretion of drugs[J].Yakugaku Zasshi, 1997, 117(8):522-541.
[9] Kusuhara, Sugiyama Y.Role of transporters in the tissueselective distribution and elimination of drugs:transporters in the livers, small intestine, brain and kidney[J].Control Release, 2002, 78(1/3):43-54.
[10] Slitt AL, Cherrington NJ, Hartley DP, et al.Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels[J].Drug Metab Dispos, 2002, 30(2):212-219.
[11] Suji A.Biopharmaceutical studies on molecular mechanisms of membrane transport[J].Yakugaku Zasshi, 2002, 122(12):1037-1058.
[12] Henry J, Binder, Leonard A, et al.The effect of inhibitors of renal transport on the small intestine[J].J Clin Invest, 1966, 45(12):1854-1854.
[13] Chen ZY, Zheng QS, Sun RY.Functions of DAS software for pharmacological calculation[J].Chin J Pharmacol Ther, 2002, 7(5):562-564.
[14] Yabuuchi H, Tamai I, Morita K, et al.Hepatic sinusoidal membrane transport of anionic drugs mediated by anion transport Npt1[J].Pharmacol Exp Ther, 1998, 286(3): 1391-1396.
[15] Vladic A, Strikic N, Jurcic D, et al.Homeostatic role of the active transport in elimination of [³H] benzylpenicillin out of the cerebrospinal fluid system[J].Life Sci, 2000, 67(19):2375-2385.
[16] Guji A, Nishiya H, Aoki M, et al.Glutathione S-transferases as a cefpiramide binding protein in rat liver[J].Pharmacol toxicol, 1995, 76(3):212-217.
[17] Selen A, Amidon GL, Welling PG.Pharmacokinetics of probenecid following oral dose to human volunteers[J].J Pharm Sci, 1982, 71(1):1238-1241.
[18] Sourgens H, Derendorf H, Schifferer H.Pharmacokinetic profile of cefaclor[J].Chin J Pharmacol Ther, 1997, 35(9):374-380.