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目的:研究左旋奥硝唑磷酸酯二钠及其代谢物左旋奥硝唑在比格犬静脉多次给药4周药物在体内的毒代动力学情况,为左旋奥硝唑磷酸酯二钠的安全性提供评价。方法:用HPLC-UV法测定血浆中药物的浓度,色谱柱为Venusil XBP C18柱,流动相为甲醇-30 mmol·L-1磷酸二氢钾(40∶60),流速1 ml·min-1,柱温30℃,波长319 nm,内标为甲硝唑。结果:首次静脉注射左旋奥硝唑磷酸酯二钠后低、中、高剂量组(40,100,300 mg·kg-1)的左旋奥硝唑的AUC0-24分别为(164.047±16.984),(461.867±60.782),(1 484.451±185.071)μg·ml-1·h;末次静脉注射左旋奥硝唑磷酸酯二钠后3个剂量组的左旋奥硝唑的AUC0-24分别为(185.144±23.346),(485.455±50.187)和(1 228.987±106.819)μg·ml-1·h。首次给药后,随着剂量的增加,左旋奥硝唑的CL降低,MRT、t1/2延长,说明左旋奥硝唑在比格犬体内存在一定的代谢或排泄饱和;末次给药后各组t1/2、V较首次给药降低,中、高剂量组的MRT较首次给药缩短,高剂量组CL增加,AUC0-24降低,表明高剂量对肝药酶存在轻微的诱导。结论:连续1个月给比格犬静注左旋奥硝唑磷酸酯二钠后,未见左旋奥硝唑在犬体内有明显蓄积,经过2周的恢复期,左旋奥硝唑在比格犬体内完全消除,试验过程中也未见比格犬有明显的毒性反应。
OBJECTIVE: To study the toxicokinetics of L-ornidazole phosphate disodium and its metabolite levorotatory ornidazole in Beagle dogs intravenously for four weeks. Security provides an evaluation. Methods: The concentration of the drug in plasma was determined by HPLC-UV. Venusil XBP C18 column was used with the mobile phase consisted of methanol-30 mmol·L-1 potassium phosphate monobasic (40:60) and the flow rate was 1 ml · min-1 , Column temperature 30 ℃, wavelength 319 nm, internal standard metronidazole. Results: The AUC0-24 of L-ornidazole was (164.047 ± 16.984) and (461.867 ± 60.782) after the first intravenous injection of levodinal ornidazole disodium phosphate in low, medium and high dose groups (40,100 and 300 mg · kg -1) ), (1 484.451 ± 185.071) μg · ml-1 · h respectively. After the last intravenous injection of levodropropizole disodium phosphate, the AUC0-24 of three dosages of levodinal ornidazole were (185.144 ± 23.346) and 485.455 ± 50.187) and (1 228.987 ± 106.819) μg · ml-1 · h. After the first dose, with the increase of dose, the CL of L-ornidazole decreased, and the prolongation of MRT and t1 / 2 showed that there was some metabolism or excretion of L-ornidazole in beagle dogs. After the last administration, t1 / 2, V was lower than that of the first administration. The MRT of middle and high dosage groups was shorter than that of the first administration, the CL of high dosage group was increased and AUC0-24 was lower, indicating that there was a slight induction of hepatic drug in high dosage. CONCLUSION: After intravenous injection of levodropropizole disodium phosphate to Beagle dogs for one month, no significant accumulation of levodropropizole in dogs was observed. After two weeks of recovery, Elimination of the body completely, during the test Beagle dogs have no obvious toxicity.