MEPHENYTOIN DISPOSITION AND SERUM BILE-ACIDS AS INDEXES OF HEPATIC-FUNCTION IN CHRONIC VIRAL-HEPATITIS

Background and objectives: The effect of chronic viral hepatitis on Li ver function may vary from none to hepatic failure. Changes in functio n are usually the result of impaired hepatocyte function or altered va scular now and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate de gree of hepatic metabolic dysfunction. An alternative approach is to m easure the hepatic metabolism of a highly extracted compound whose ora l clearance and systemic bioavailability are dependent on both hepatoc yte function and degree of portosystemic shunt. Methods: The stereosel ective metabolism of racemic mephenytoin (100 mg oral dose) was invest igated in 35 patients with chronic viral hepatitis and compared with 1 53 healthy subjects. The mephenytoin R/S enantiomeric ratio and cumula tive excretion of the 4'-hydroxymephenytoin metabolite in a 0- to 8-ho ur urine sample were used in addition to serum bile acid levels and pa thologic examination of biopsy specimens to assess the severity of hep atic dysfunction and portosystemic shunting. Results: The patients as a group excreted less 4'-hydroxymephenytoin and had a smaller R/S enan tiomeric ratio of mephenytoin. The two measures were discriminatory be tween the patient groups classified by either serum cholylglycine leve l or pathologic examination of biopsy specimens. Combination of the tw o measures of mephenytoin metabolism allowed the patients to be classi fied into three groups: normal hepatocyte function without portosystem ic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt. Conclusion: This study has shown the potential usefulness of mephenytoin metabolis m as a sensitive indicator of hepatic pathologic condition with an abi lity to discriminate between contributory alternative mechanisms.