The effect of valproate on the metabolism of phenobarbital in the rat.
The effect of valproate on the metabolism of phenobarbital in the rat.
复制标题
丙戊酸对大鼠苯巴比妥代谢的影响。
DOI：
10.1023/a:1015876727795
复制
发表时间：
1992
影响因子：
3.7
通讯作者：
Levy,RH
中科院分区：
文献类型：
--
作者：
Anderson,GD;Levy,RH
丙戊酸已被证明与所有主要抗癫痫药物相互作用。与苯巴比妥的相互作用最具临床意义。在体内大鼠和体外肝脏灌注系统中评估了相互作用的机制。苯巴比妥和对羟基苯巴比妥（PbOH）在有或没有丙戊酸治疗的情况下给药。在体内，给予 PbOH 后，丙戊酸对未改变的 PbOH 的肾清除率 (40%) 和其葡萄糖醛酸结合物的形成清除率 (ClF) (44%) 产生显着抑制。当与苯巴比妥合用时，丙戊酸引起苯巴比妥总血浆清除率显着降低（95.4±29.0至65.8±20.2ml/hr/kg），但对苯巴比妥肾清除率或PbOH的ClF没有明显影响。丙戊酸确实对次要代谢物间羟基苯巴比妥的形成产生显着抑制（50%）。丙戊酸盐的最大作用似乎是对苯巴比妥消除的未知途径。在分离的灌注大鼠肝脏中，测定了 PbOH 及其葡萄糖苷酸结合物的 ClF。丙戊酸钠导致 PbOH 的 ClF 略有下降（10%）但显着。从体内观察到，丙戊酸盐最显着的影响是对 PbOH 葡萄糖醛酸苷的 ClF 的影响（降低 66%）。总之，丙戊酸对 PbOH 形成的抑制不能完全解释在治疗中添加丙戊酸时苯巴比妥血浆浓度升高的原因。要完整了解该机制，需要完整计算大鼠或人类的苯巴比妥剂量。
Valproate has been shown to interact with all major antiepileptic drugs. The interaction with phenobarbital is the most clinically significant. The mechanism of the interaction was evaluated in the in vivo rat and in vitro liver perfusion system. Phenobarbital and parahydroxyphenobarbital (PbOH) were administered with and without valproate treatment. In vivo, after administration of PbOH, valproate caused a significant inhibition of both the renal clearance of unchanged PbOH (40%) and the formation clearance (ClF) of its glucuronide conjugate (44%). When coadministered with phenobarbital, valproate caused a significant decrease in the total plasma clearance of phenobarbital (95.4 ± 29.0 to 65.8 ± 20.2 ml/hr/kg), with no apparent effect on the phenobarbital renal clearance or the ClF of PbOH. Valproate did cause a significant inhibition (50%) of formation of a minor metabolite, metahydroxyphenobarbital. The largest effect of valproate appears to be on unknown pathways of phenobarbital elimination. In the isolated perfused rat liver, the ClF of PbOH and its glucuronide conjugate were determined. Valproate caused a small (10%) but significant decrease in the ClF of PbOH. As seen in vivo, the most significant effect of valproate was on the ClF of the PbOH glucuronide (66% decrease). In conclusion, inhibition of PbOH formation by valproate cannot account entirely for the increased plasma concentrations of phenobarbital that occur when valproate is added to therapy. A complete understanding of the mechanism will require a complete accounting of the phenobarbital dose in rat or in humans.