阿奇霉素对大鼠灌服华法林的药效学和药动学的影响

目的：研究抗生索阿奇霉素对大鼠灌服华法林的药效学指标凝血酶原时间（PT）和国际标准化比值（INR）以及药动学指标血药浓度的影响。方法：将SD大鼠随机分成两组：单用华法林组（A组）和华法林＋阿奇霉素合用组（B组），每组大鼠灌胃给予华法林0．2mg·kg^-1，每日1次，连续613，其中B组大鼠在第6日最后1次灌胃给予华法林后立即腹腔注射阿奇霉素80mg·kg^-1，且开始计时，分别于0．25、0．5、1．5、2．5、3．5、5、7、10、13小时采血，测定PT，计算INR。并建立HPLC法，测定华法林血药浓度。结果：从5小时开始，B组大鼠的胛值较A组显著增大（P〈0．05），INR值最高可达7．5；B组大鼠的华法林药动学参数咒。较A组显著延长（P〈0．01），其他药动学参数无显著性差异；两组大鼠的INR-C曲线都呈逆时针走向，且B组的逆时针效应更甚。结论：阿奇霉素与华法林合用可发生药效学和药动学相互作用，增强华法林的抗凝作用，增加用药者的出血风险，故临床上两药合用时应密切监测用药者的INR值，避免严重不良反应的发生。

Effects of Azithromycin on the Pharmacokinetics and Pharmacodynamics of Oral Warfarin in Rats

Objective： To investigate the effects of azithromycin on prothrombin time （PT） and International Normalized Ratio （INR） as pharmacodynamics index and plasma concentration of warfarin as pharmaeokinetics index in rats treated orally with warfarin. Methods： 16 healthy SD rats were randomly divided into two groups： group A（ n = 8）, given warfarin alone and group B（ n = 8）, given warfarin in combination with azithromycin. Rats in both groups were given with warfarin （0.2 mg·kg^-1, po, qd） for 6 d. On day 6, rats in group B were administered simultaneously with azithromycin （80 mg·kg^-1, ip） and timing started. Blood in rats in both groups was collected respectively at 0.25, 0.5, 1.5, 2.5, 3.5, 5, 7, 10, 13 h. PT and INR of rats were measured using thromboplastin reagent. The plasma concentration of warfarin was determined by HPLC. Results： Compared with group A, PT value of rats started to increase significantly at 5 h （P 〈0.05）, the maximum INR value reached 7.5 and Tmax of warfarin was significantly prolonged （P 〈0.01） in group B. However, other pharmacokinetic parameters showed no significant difference between both groups. The INR-C curves in two groups showed counter-clock-wise hysteresis loop, which was more significant in group B. Conclusion： The combination of warfarin with azithromycin could induce pharmacodynamic and pharmacokinetic interactions to enhance warfarin＇s anticoagulant activity resulting in the increased hemorrhage risk. So the INR of the patient codministered with both the drugs should be closely monitored to avoid serious adverse reaction.