Hepatic functions phenobarbital

Phenobarbital is metabolized by CyP 2C19 to p-hydroxy-phenobarbital, which is largely excreted as the glucuronide (by UGT). When renal and hepatic function are decreased, patients experience decreased clearance of the drug. Alcohol, carbamazepine, other barbiturates, and rifampin induce oxidative enzymes (CyP 2C19 and 2C9) this induction results in increased metabolism of phenytoin, reduced serum concentration of phenobarbital, and a reduced pharmaco-... 

Klingensmith JS, Mehendale HM. 1983a. Destruction of hepatic mixed-function oxygenase parameters by CC14 in rats following acute treatment with chlordecone, mirex, and phenobarbital. Life Sci 33(23) 2339-2348. 

Chloroethanes have been shown to undergo dechlorination by an enzyme system that is similar to the hepatic microsomal mixed function oxidase system (Van Dyke and Wineman 1971). Dechlorination was inducible by phenobarbital and required oxygen and NADPH. However, dechlorination also required a factor from the cytosolic fraction of the liver homogenate for optimal dechlorinating activity. In terms of structural requirements, dechlorination was enhanced if the carbon atom containing the chlorine had only one hydrogen. In a microsomal incubation, 13.5% of... 

Acute hepatocellular necrosis. This reaction varies from a transient disturbance of liver function tests to acute hepatitis. It can be induced by several drugs including general anaesthetics (halothane), antiepileptics (carbamazepine, phenytoin, sodium valproate, phenobarbital), antidepressants (MAO inhibitors), antiinflammatory drugs (indomethacin, ibuprofen), antimicrobials (isoniazid, sulphonamides, nitrofurantoin) and cardiovascular drugs (methyldopa, hydralazine). 

Much of the evidence, however, is based on prolonged plasma half-lives of drugs that are metabolized totally or mainly by hepatic micrasomal enzymes (e.g antipyrine, phenobarbital, acetaminophen). In evaluating the effect of age on drug metabolism, one must differentiate between normal" loss of enzymatic activity with aging and the effect of a disea.sed iiver from hepatitis, cirrhosis, etc., plus decreased renal function, becau.se much of the water-soluble conjugation products are excreted in the liver. 

Absorption of oral phenobarbital is slow but complete. The time at which peak plasma concentrations are reached is widely variable and ranges from 4 to 10 hours after the dose. Phenobarbital is 40% to 60% bound to plasma proteins. CyP 2C19 is the primary hepatic enzyme involved in metabolism, producing an elimination half-life of 70 to 100 hours metabolism is age dependent (children average 70 hours, geriatric patients 100 hours). Because hepatic metabolism is the primary organ of elimmation, reduced liver function results in prolonged half-life. 

Govindwar SP, Kachole MS, Pawar SS. 1988. Effect of caffeine on the hepatic microsomal mixed function oxidase system during phenobarbital and benzo[a]pyrene treatment in rats. Toxicol Lett 42(2) 109-115. 

As with phenobarbital, serious toxicity for primidone is rare, although it may cause disabling sedation. Irritability, and decreased mental functioning In a number of persons. Ataxia, dysphoria, idiosyncratic rash, leukopenia, agranulocytosis, lymphadenopathy, hepatitis, and a systemic lupus erythematosus-like syndrome have been reported adverse effects for primidone. Deficiencies of folic acid and of vitamins D and K are possible with long-term therapy of primidone, as Is a folate-responsive megaloblastic anemia. Measurement of the complete blood cell count should be performed at 6-month intervals (40). 

A 99TC-IDA derivate isotope scan (scintigraphy) can also differentiate between BA and neonatal hepatitis. Phenobarbital must be administered for 3-5 days to jump-start hepatocellular function. If the tracer reaches the duodenum, biliary atresia can be excluded. However, some authors recommend imaging at 24 h to exclude delayed excretion. Scintigraphy has 50%-75% specificity and 90%-100% sensitivity for BA (Petersen and Ure 2003) (Fig. 4.2c,d). 

Studies of the effects of typical inducers of mixed-function oxidase activity on DMN demethylation have also produced contradictory results. One group found that 3-methylcholanthrene and other PAH inhibited rat hepatic DMN demethylase activity (and DMN carcinogenicity) (474, 476), while others observed an increase in activity (136, 331, 374). Similar results were obtained in studies with Aroclor 1254, which was shown by one group to induce DMN demethylase activity in mouse liver (90), while other investigators found no change in activity (14). Contradictory results were also observed with phenobarbital (10, 13, 331, 374). These contradictions appear to have been at least partially resolved by the discovery of two hepatic forms of DMN demethylase. These two forms of DMN demethylase appear to respond differently to pretreatment with typical enzyme inducers one form is induced and the other repressed (11). The two different forms catalyze DMN demethylation at low substrate concentrations (0-4 mM)... 

Thioacetamide is almost entirely converted in vivo by rats to acetamide, which is subsequently converted to acetate. Liver slices are 3 times more active than kidney slices in this metabolism. The ability of the liver to metabolize thioacetamide so rapidly has been related to the chemicaPs hepatocarcino-genicity. However, the ultimate carcinogen is not thought to be acetamide, since thioacetamide causes hepatomas at a small fraction of the dose that is necessary for the carcinogenicity of acetamide. In phenobarbital-pretreated rats, thioacetamide, sodium diethyldithiocarbamate, thiourea, thiouracil (430), 6-methylthiouracil (431), and 6-propylthiouracil (432) cause a loss in hepatic cytochrome P-450 or inhibit the oxidiative A -demethylation of benzphetamine. This has been related to the mixed-function-oxidase-catalyzed release and covalent binding of a reactive form of sulfur to cellular components (Figure 6). 

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