Impairment of drug elimination in patients with liver disease.

An attempt has been made to investigate drug elimination in patients with liver disease. Antipyrine was chosen as a model drug. The patients were divided into three groups depending upon clinical, biochemical, radiologic and histologic findings; (1) mild (Idiopathic portal hypertension, extrahepatic portal vein obstruction and Gilbert's syndrome); (2) moderate (Budd-Chiari syndrome and amoebic liver abscess); (3) severe (acute hepatitis, chronic active hepatitis and cirrhosis). A prolongation in antipyrine half-life (t1/2) was observed in 108 patients with liver disease (24.59 +/- 1.72 h) as compared to 12 controls (11.63 +/- 0.86 h). Similarly, metabolic clearance rate was decreased in all liver disorders. Among liver function tests, antipyrine t1/2 showed a significant correlation with serum albumin and prothrombin time index. After phenobarbitone administration, antipyrine clearance studied in 37 patients showed a significant decrease in t1/2 and an increase in MCR. Antipyrine t1/2 in 26 patients after recovery was comparable to those of controls.

In vitro drug metabolism in humans with different liver diseases.

In vitro drug metabolism studies were carried out in 97 patients with liver disease. Drug-metabolizing enzymes (aminopyrine N-demethylase and bilirubin UDP-glucuronyl transferase) were estimated in livers obtained at the time of biopsy with a Menghini needle. The patients were divided into three groups depending on clinical, biochemical, radiologic, and histologic findings: (i) mild (non-cirrhotic portal fibrosis and extrahepatic portal vein obstruction), (ii) moderate (Budd-Chiari syndrome and amebic liver abscess), (iii) severe (acute hepatitis, chronic active hepatitis, and cirrhosis). Aminopyrine N-demethylase was decreased in all liver disorders as compared to ten control liver samples. Bilirubin UDP-glucuronyl transferase was significantly lower in all liver disorders except for amebic liver abscess and extrahepatic portal vein obstruction. Both the enzymes in (i) and (ii) groups were significantly higher than in group (iii). A significant correlation was obtained between the two enzymes.

Levels of arsenic in liver cirrhosis.

The present studies were conducted to determine the arsenic levels in liver specimens obtained at autopsy from human subjects suffering from liver cirrhosis. Arsenic content was determined using the neutron activation analysis technique. Increased levels of arsenic were found in cirrhotic liver samples including alcoholic cirrhosis. Various surveys were conducted in different places to find the cause for high arsenic in patients with alcoholic cirrhosis. It was found that patients were consuming 'home-made brew' which was contaminated with arsenic. The study suggests that elevated levels of arsenic may be associated with liver damage in cirrhotic patients.

Lymphocyte subpopulation in acute viral hepatitis.

Studies of peripheral blood lymphocytes were performed in 41 patients with acute viral hepatitis, in grade III-IV coma; 16 patients were in the third trimester of pregnancy. There were significant reductions in absolute lymphocyte count and T cell number in patients who succumbed to the disease, when compared with those who survived. B cell counts were similar in the two groups and migration inhibition test with BCG antigen was normal. It is postulated that a decrease in the number of cells interacting in cell-mediated immune reactions is related to prognosis in acute viral hepatitis.

Impairment of hepatic drug metabolism in patients with acute viral hepatitis.

Hepatic drug metabolism in patients with acute viral hepatitis was investigated under different conditions: pregnancy, postpartum, non-pregnancy, and among males. Liver function tests were altered in all of these conditions. The relationship between in vivo and in vitro drug metabolism was studied in twenty-two patients using diagnostic liver needle biopsies by comparing the drug metabolising enzymes (aminopyrine-N-demethylase and bilirubin-UDP-glucuronyl transferase) in these biopsies with the elimination kinetics of antipyrine. Drug clearance tests were repeated in the patients who had recovered. All patients gave altered liver function tests results. Antipyrine half-life was significantly higher in females as compared to males. Among females, it was maximum in the pregnant group. Activities of drug metabolising enzymes were found to be significantly lower in liver biopsy material. The half-life of antipyrine showed a significant correlation with drug metabolising enzymes. After recovery patients showed a normal antipyrine half-life.

Antipyrine clearance, aminopyrine N-demethylase, and bilirubin UDP-glucuronyl transferase activity in patients with amoebic liver abscess.

Three indices of drug metabolism, antipyrine clearance in vivo, and aminopyrine N-demethylase and bilirubin UDP-glucuronyl transferase activity in liver biopsies, were studied in fifteen patients with amoebic liver abscess (with and without jaundice). The mean (+/- S.E.) antipyrine half-life in patients with jaundice was 21.64 (+/- 1.52) h and in patients without jaundice was 19.36 (+/- 0.93) h. It was significantly prolonged in both groups of patients as compared to controls (11.63 +/- 0.86 h). It showed a good correlation with serum albumin (p less than 0.01), prothrombin time index (p less than 0.01), and aminopyrine N-demethylase (p less than 0.05). Aminopyrine N-demethylase was found to be decreased in patients without jaundice but no significant change could be observed in patients with jaundice. Bilirubin UDP-glucuronyl transferase showed no significant change in either of the groups.

Pharmacokinetic study of chloramphenicol in patients with liver disease.

The pharmacokinetics of intravenous chloramphenicol has been studied in 42 patients with liver disease and in 8 controls. The half-life of chloramphenicol (t 1/2) was increased in the various liver disorders, the metabolic clearance rate (MCR) and apparent volume of distribution (Vd) were decreased and the area under the time - concentrations curve (AUC) showed an increase. The t 1/2 of chloramphenicol showed a significant correlation with serum albumin and prothrombin time index.