Daemen M J, Vervoort-Peters H T, Thijssen H H
J Pharm Sci. 1986 Mar;75(3):238-40. doi: 10.1002/jps.2600750305.
Saturable hepatic uptake processes may account for the apparent dose-dependent clearance of 4-hydroxycoumarins. We investigated the dose dependent clearance and dose dependent liver distribution of the (S)-enantiomer of acenocoumarol (4-hydroxy-3-[1-4-nitrophenyl)-3-oxobutyl]coumarin) in the rat applying the in situ liver biopsy technique. The drug was administered by constant-rate infusion. At infusion rates below 0.6 microgram/min, blood clearance appeared to be dose dependent, i.e., clearance of (S)-acenocoumarol declined gradually from 6.5 mL/min at a 0.15 microgram/min infusion rate to 3.9 mL/min at a 0.6 micrograms/min infusion rate. From 0.6 microgram/min up to the highest input tested, i.e., 15 micrograms/min, clearance was almost constant, 3.5 mL/min. At low infusion rates the steady-state liver concentration of (S)-acenocoumarol rose steeply in a convex way with infusion. Scatchard analysis of steady-state liver concentrations in relation to steady-state blood concentrations revealed a hepatic binding site for (S)-acenocoumarol, exhibiting a capacity of 1.4 microgram/g of liver tissue.
肝脏的饱和摄取过程可能是4-羟基香豆素表观剂量依赖性清除的原因。我们应用原位肝活检技术，研究了醋硝香豆素（4-羟基-3-[1-（4-硝基苯基）-3-氧代丁基]香豆素）的（S）-对映体在大鼠体内的剂量依赖性清除和剂量依赖性肝脏分布。药物通过恒速输注给药。在输注速率低于0.6微克/分钟时，血液清除率似乎具有剂量依赖性，即（S）-醋硝香豆素的清除率从0.15微克/分钟输注速率时的6.5毫升/分钟逐渐下降至0.6微克/分钟输注速率时的3.9毫升/分钟。从0.6微克/分钟直至测试的最高输入速率（即15微克/分钟），清除率几乎恒定，为3.5毫升/分钟。在低输注速率下，（S）-醋硝香豆素的稳态肝脏浓度随着输注呈凸形急剧上升。对稳态肝脏浓度与稳态血液浓度进行Scatchard分析，结果显示存在一个（S）-醋硝香豆素的肝脏结合位点，其结合容量为1.4微克/克肝组织。
