Phenobarbital, inhibition

Our results of the effects of phenobarbital on the CD-diet-induced lipid peroxidation are analogous to the earlier findings that phenobarbital inhibited a CD diet-induced cell proliferation. Since the combination of phenobarbital and a CD diet resulted in a synergistic effect on promotion, the findings support the notion that the promoting effects of a CD diet and phenobarbital are mediated through different mechanisms. While sustained liver cell... 

Phenobarbital inhibits posttetanic potentiation and especially raises the seizure threshold. The precise mechanism of action of phenobarbital is not known, though two dissimilar mechanisms have been advanced. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Animal studies indicate that trichloroethylene can sensitize the heart to epinephrine-induced arrhythmias. Other chemicals can affect these epinephrine-induced cardiac arrhythmias in animals exposed to trichloroethylene. Phenobarbital treatment, which increases the metabolism of trichloroethylene, has been shown to reduce the trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and Carlson 1979), whereas high concentrations of ethanol, which inhibits trichloroethylene metabolism, have been found to potentiate trichloroethylene-epinephrine-induced arrhythmias in rabbits (White and Carlson 1981). These results indicate that trichloroethylene itself and not a metabolite is responsible for the epinephrine-induced arrhythmias. In addition, caffeine has also been found to increase the incidence of epinephrine-induced arrhythmias in rabbits exposed to trichloroethylene (White and Carlson 1982). 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Primary adrenal insufficiency (Addison s disease) most often involves the destruction of all regions of the adrenal cortex. There are deficiencies of cortisol, aldosterone, and the various androgens. Medications that inhibit cortisol synthesis (e.g., ketoconazole) or accelerate cortisol metabolism (e.g., phenytoin, rifampin, phenobarbital) can also cause primary adrenal insufficiency. 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

Ethanol increases phenobarbital metabolism, but valproic acid, cimeti-dine, and chloramphenicol inhibit its metabolism. 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

Metofluthrin (I) The committee determined that the new data were sufficient to support a mitogenic mode of action for the development of liver tumors in rats exposed to metofluthrin in the carcinogenicity study. The report summarized mode of action study data that characterized effects such as increased P450 enzyme levels, increased smooth endoplasmic reticulum, hepatocellular hypertrophy, hepatocellular proliferation, and inhibition of intracellular communication, which were described as steps leading to tumor development via a nongenotoxic mechanism (i.e., mitogenicity). Some of these studies used sodium phenobarbital as a positive control,... 

Phenobarbital-like promotion Crystalluria, carbonic anhydrase inhibition, urine pH extremes, melamine, saccharine, carbonic anhydrase inhibitors, dietary phosphates... 

Enzymatic-metabolic activation (in part unknown)/phenobarbital-like promotion Hepatic enzyme induction, thyroid enzyme inhibition/axazepam, amobarbital, sulphonamides, thioureas Gastric secretory suppression, gastric atrophy induction (climetidine, omeprazole, butachlor... 

Figure 32.4 Percentage Inhibition of Labelled Phenobarbital Binding by Added Unlabelled phenobarbital.

RT-PCR often brain tumors reveals none positive for CYP3A4 (Knupfer et al., 1999). Phenobarbital induces CYP3A1 mRNA in rat striatum and cerebellum (Schilter et al., 2000). Rat and human brain microsomes demethylate amitriptyline. Chemical and antibody inhibition suggests CYP3A4 is responsible (Voirol et al., 2000). 

Reddy TV, Daniel FB, Lin EL, et al. 1992. Chloroform inhibits the development of diethylnitrosamine-initiated, phenobarbital-promoted gamma-glutamyltranspeptidase and placental form glutathione S-transferase-positive foci in rat liver. Carcinogenesis 13(8) 1325-1330. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In particular, certain drugs may induce the metabolism of bupropion (eg, carbamazepine, phenobarbital, phenytoin) while other drugs may inhibit the metabolism of bupropion (eg, cimetidine, ritonavir). 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

Type II Multiple actions enhance GABAergic inhibition, reduce T-calcium currents, and possibly block SRF Valproic acid Benzodiazepines Phenobarbital Primidone... 

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