Urinary six-thiouric acid after oral six-mercaptopurine in patients with chronic active hepatitis

Chronic active hepatitis is an inflammatory disease of the liver of unknown etiology often associated with a pronounced immune response. Current therapy is non-specific and is directed toward suppression of inflammation and the exaggerated immune response. Corticosteroids are the main agents used in controlling the disease but the prominent side effects are disturbing to many patients and are sometimes of serious clinical significance. To reduce the steroid dose other immunosuppressant drugs are occasionally used in addition to steroids and sometimes these agents are used alone. Patients with chronic active hepatitis have increased sensitivity to 6-mercaptopurine and azathioprine, the most popular of the immunosuppressant agents. These patients show signs of drug toxicity at doses one-third to one fourth that of patients without liver disease. This toxicity has included anorexia, jaundice, hepatic come, and bone marrow suppression and appears to be related to both the dose of the drug and the severity of the liver disease. The reason for the increased sensitivity is unknown. This study attempts to evaluate indirectly the activity of xanthine oxidase, the major enzyme involved in the metabolism of 6-mercapto-purine, in patients with chronic active hepatitis. Six of these patients were challenged with a single oral dose of 6-mercaptopurine, 2.3-2.9 mg/kg. The urinary excretion of 6-thiouric acid, the major metabolite of 6-MP, was measured for 24 hours after the drug was given. Four patients without liver disease served as control subjects. They received a single oral dose of 6-mercaptopurine, 2.3 mg/kg. There was no significant difference between the two groups in the percent of dose excreted as 6-thiouric acid in the 24 hour collection period and in the excretion of uric acid. However, within the hepatitis group the excretion of 6-thiouric acid varied inversely with the duration and severity of the disease. Urinary 6-thiouric acid excretion in three control subjects may have been reduced due to factors unrelated to liver disease. One control patient with granulomatous disease of the bowel excreted the smallest amount of 6-thiouric acid of all patients and id so at the slowest rate. It is possible that the intestinal absorption of 6-mercaptopurine is abnormal in this patient. The observation may be useful in planning and interpreting clinical trials of 6-mercaptopurine therapy of granulomatous gastrointestinal disease.