Arns P A, Adedoyin A, DiBisceglie A M, Waggoner J G, Hoofnagle J H, Wilkinson G R, Branch R A
Vanderbilt University School of Medicine, Department of Pharmacology, Nashville, Tenn., USA.
Clin Pharmacol Ther. 1997 Nov;62(5):527-37. doi: 10.1016/S0009-9236(97)90048-5.
The effect of chronic viral hepatitis on liver function may vary from none to hepatic failure. Changes in function are usually the result of impaired hepatocyte function or altered vascular flow and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate degree of hepatic metabolic dysfunction. An alternative approach is to measure the hepatic metabolism of a highly extracted compound whose oral clearance and systemic bioavailability are dependent on both hepatocyte function and degree of portosystemic shunt.
The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was investigated in 35 patients with chronic viral hepatitis and compared with 153 healthy subjects. The mephenytoin R/S enantiomeric ratio and cumulative excretion of the 4'-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used in addition to serum bile acid levels and pathologic examination of biopsy specimens to assess the severity of hepatic dysfunction and portosystemic shunting.
The patients as a group excreted less 4'-hydroxymephenytoin and had a smaller R/S enantiomeric ratio of mephenytoin. The two measures were discriminatory between the patient groups classified by either serum cholylglycine level or pathologic examination of biopsy specimens. Combination of the two measures of mephenytoin metabolism allowed the patients to be classified into three groups: normal hepatocyte function without portosystemic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt.
This study has shown the potential usefulness of mephenytoin metabolism as a sensitive indicator of hepatic pathologic condition with an ability to discriminate between contributory alternative mechanisms.
慢性病毒性肝炎对肝功能的影响可能从无到肝功能衰竭不等。功能变化通常是肝细胞功能受损或血管血流及结构改变的结果。传统的肝功能检查通常无法区分这些机制的作用，也无法表明肝代谢功能障碍的程度。另一种方法是测量一种高摄取化合物的肝代谢，其口服清除率和全身生物利用度取决于肝细胞功能和门体分流程度。
对35例慢性病毒性肝炎患者研究了消旋美芬妥英（口服剂量100mg）的立体选择性代谢，并与153名健康受试者进行比较。除了血清胆汁酸水平和活检标本的病理检查外，还使用美芬妥英的R/S对映体比率以及0至8小时尿液样本中4'-羟基美芬妥英代谢物的累积排泄量来评估肝功能障碍和门体分流的严重程度。
作为一个整体的患者组排泄的4'-羟基美芬妥英较少，美芬妥英的R/S对映体比率较小。这两项指标在根据血清甘氨胆酰甘氨酸水平或活检标本病理检查分类的患者组之间具有区分性。美芬妥英代谢的两项指标相结合可将患者分为三组：无门体分流的正常肝细胞功能、有门体分流的正常肝细胞功能、有或无门体分流的低肝细胞功能。
本研究表明美芬妥英代谢作为肝病理状况的敏感指标具有潜在用途，且有能力区分不同的作用机制。
