Chow H H, Lalka D
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo.
Drug Metab Dispos. 1992 Mar-Apr;20(2):288-94.
The effects of vitamin K3 treatment on the pharmacokinetics and metabolism of (+)-propranolol and the consequences of hepatic injury associated with vitamin K3 treatment were examined in groups of male Sprague-Dawley rats. When vitamin K3 (20 mg/kg) in polyethylene glycol 300 (PEG 300) was coinfused with (+)-propranolol (2 mg/kg) into the pyloric vein (a tributary flowing directly into the hepatic portal vein), a significant decrease in the intrinsic clearance of total drug (CLint) from 94.1 +/- 50.1 to 32.9 +/- 11.5 ml/min/kg was observed (p less than 0.01 vs. vehicle control). However, a lower dose of vitamin K3 (2 mg/kg in PEG 300) had little effect on this parameter. Interestingly, the PEG 300 vehicle control group exhibited a significantly (p less than 0.05) higher CLint than that observed in a saline control group (94.1 +/- 50.1 vs. 45.9 +/- 13.7 ml/min/kg). This difference appeared to be due to an increase in the free fraction of propranolol caused by PEG 300, because in vitro addition of this solvent to serum (at estimated in vivo concentrations) with or without added vitamin K3 doubled propranolol free fraction. Furthermore, rats that received the high dose vitamin K3 (20 mg/kg) treatment exhibited a pronounced increase in the serum concentration of enzymes of hepatic origin (alanine aminotransferase and sorbitol dehydrogenase) and in the incidence of hepatic necrosis. It was also observed that high-dose vitamin K3 treatment caused only minor changes in the urinary recovery of propranolol metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)
在雄性斯普拉格-道利大鼠组中，研究了维生素K3治疗对（+）-普萘洛尔药代动力学和代谢的影响，以及与维生素K3治疗相关的肝损伤后果。当将聚乙二醇300（PEG 300）中的维生素K3（20 mg/kg）与（+）-普萘洛尔（2 mg/kg）共同注入幽门静脉（直接流入肝门静脉的一条支流）时，观察到总药物内在清除率（CLint）从94.1±50.1显著降低至32.9±11.5 ml/min/kg（与溶媒对照组相比，p<0.01）。然而，较低剂量的维生素K3（PEG 300中的2 mg/kg）对该参数影响不大。有趣的是，PEG 300溶媒对照组的CLint显著高于生理盐水对照组（p<0.05）（94.1±50.1对45.9±13.7 ml/min/kg）。这种差异似乎是由于PEG 300导致普萘洛尔游离分数增加，因为在体外向含有或不含有维生素K3的血清（按估计的体内浓度）中添加该溶剂会使普萘洛尔游离分数增加一倍。此外，接受高剂量维生素K3（20 mg/kg）治疗的大鼠肝源性酶（丙氨酸转氨酶和山梨醇脱氢酶）的血清浓度以及肝坏死发生率显著增加。还观察到高剂量维生素K3治疗仅使普萘洛尔代谢物的尿回收率发生轻微变化。（摘要截断于250字）
