Hepatic Metabolic Function Research Articles

Hepatic First-pass Metabolism in Liver Disease

Many drugs are known or suspected of having substantial first-pass hepatic metabolism in humans, and have low oral bioavailability on this basis. Hepatic disease might alter (increase) bioavailability by either or both of 2 mechanisms: decreased hepatic extraction due to impaired hepatic drug metabolising activity, or portosystemic shunting. Few studies have examined the effect of liver diseases on bioavailability, and even fewer have attempted to directly measure hepatic extraction of drugs in liver disease. Data are conflicting, with some evidence to suggest that hepalocyte function is preserved in moderate cirrhosis, while other evidence suggests a decrease in hepatic metabolic function. Several studies show relative preservation of systemic clearance in the face of substantial increases in bioavailability, suggesting that the hepatic arterial blood supply of the liver is an important determinant of systemic clearance in cirrhotic patients.

Mechanism of secretion of biliary lipids: Role of a microtubular system in hepatocellular transport of biliary lipids in the rat

The role of microtubules in the hepatocellular transport of biliary lipids has been investigated utilizing the actively secreting isolated rat liver perfusion model and the microtubular blocking agents, vinblastine and colchicine. The liver was perfused with sodium taurocholate (12 μmoles per hr) to produce active lipid secretion for 90 min before vinblastine administration and for 60 min before colchicine. The vinblastine-and colchicine-treated livers were then perfused for an additional 60 and 120 min, respectively. Two concentrations of vinblastine were used: (1) 1 × 10−5 m and (2) 5 × 10−5 M; the concentration of colchicine was 5 × 10−6 M. Control groups received isotonic saline. Specific and nonspecific hepatic metabolic functions, including perfusion flow rates, protein and lecithin synthesis, bile acid uptake, and cytidine diphosphate choline 1,2-diglyceride transferase activity were not significantly altered by vinblastine. Similarly, colchicine administration had no effect on flow rates, protein synthesis, biliary lecithin metabolism, oxygen consumption, and β-hydroxybutyrate perfusate concentrations; colchicine did depress perfusate acetoacetate concentration by 33%. These viability criteria validate the metabolic integrity of this model for studying biliary lipid transport. Biliary lipid secretion and bile flow were significantly inhibited by both blocking agents at all concentrations. The selective effect on phospholipid and cholesterol output, however, was greater than for either bile acids or flow. These data support the concept that biliary lipids are secreted by a heterogeneous and complex transport process and also provide definitive evidence that the hepatocyte microtubular network participates in the translocation of lipids from microsomes to the canalicular membrane.

Hepatic aminopyrine N-demethylase, acetanilide hydroxylase and lipid peroxidation in young growing rats during the treatment of insecticides.

Halogenated hydrocarbon insecticides and their metabolites are knovm to alter the activity of microsomal enzymes(HART et a1.1963, HART and FOUTS 1963, 1965, WELCH et a1.1967, BUNYAn and PAGE 1973). in contrast to the halogenated hydrocarbons there are very few reports regarding the effect of organophosphorus and carbamate insecticides on microsomal drug metabolizing enzymes. Hepatic drug metabolism has been found to be decreased by malathion in mice and rats (STEVENS et al. 1972, RA0 and ANDERS 1973, STEVENS and GREENE 1973). Very recently, STEVENS and GREENE (1974) have showed that subacute administration of insecticides resulted in induction of hepatic drug metabolism and mixed function oxidase systems in rats! however, WEBER et a1,(1974) have reoorted that parathion inhibited the metabolism of benzo(a)pyrene in rat liver and intestine. Our earlier investigations have reported an increase in drug metabolizing enzymes and lipid peroxidation during Take20 administration and a decrease in drug metabolism followed by an increased lipid peroxidation during Baygon administration in young growing rats (MAKHIJA and PAWAR 1974,1975). A literature review indicates a paucity of toxicological data and hence the present experiments were planned to investigate the effect of Take-20 (0,0dimethyl malathion) and Baygon on hepatic drug metabolism and lipid peroxidation in young growing rats.

Urinary D-glucaric acid: An index of hepatic microsomal enzyme activity in human females

The administration of phenobarbital, a known hepatic microsomal enzyme induction agent, to human females causes a significant increase in urinary D-glucaric acid. Similar increases occur following administration of progesterone. These observations indicate that urinary glucaric acid reflects hepatic metabolic function and can be used as an index of microsomal enzyme activity in the human female.