Liver Metabolism Enzymes

CARMUSTINE ANTIEPILEPTICS -PHENOBARBITAL 1 plasma concentrations of carmustine and 1 anti-tumour effect in animal experiments Attributed to induction of liver metabolizing enzymes of carmustine by phenobarbitone, particularly with long-term therapy Avoid concurrent use. As this study did not show any interaction with phenytoin, phenytoin may be a suitable alternative antiepileptic... 

The first-pass effect refers to presystemic elimination by the gut or liver. After being absorbed into enterocytes, compounds can be metabolized by gut and liver metabolic enzymes or effluxed by transporters before they reach the systemic circulation. 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

The co-administration of drugs which induce the metabolic enzymes in the liver or small intestine can reduce the plasma concentrations of drugs which are substrates of the enzyme, leading to reduced drug effects. For example, the plasma concentrations of many drugs which are substrates of the enzyme CYP3A4, such as cyclosporine, are decreased by coadministration of rifampicin, which is an inducer of CYP3A4. 

Data from both in vivo and in vitro systems showed PbTx-3 to have an intermediate extraction ratio, indicating in vivo clearance of PbTx-3 was equally dependent upon liver blood flow and the activity of toxin-metabolizing enzymes. Studies on the effects of varying flow rates and metabolism on the total body clearance of PbTx-3 are planned. Finally, comparison of in vivo metabolism data to those derived from in vitro metabolism in isolated perfused livers and isolated hepatocytes suggested that in vitro systems accurately reflect in vivo metabolic processes and can be used to predict the toxicokinetic parameters of PbTx-3. 

Nakajima T, Wang RS, Murayama N, et al. 1990b. Three forms of trichloroethylene-metabolizing enzymes in rat liver induced by ethanol, phenobarbital, and 3-methylcholanthrene. Toxicol Appl Pharmacol 102 546-552. 

E (1997) Mechanism of action of dietary chemoprotective agents in rat liver induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism . Carcinogenesis, 18 1729-38. 

To date, there is very little known about if and how phytochemicals modulate the metabolism of GIT tissues other than the liver. Of particular interest are the xenobiotic metabolizing enzymes of the GIT, which are involved with transformation of drugs and toxins. Whereas the metabolic activities of the resident microflora dominate in the large intestine, mucosal enzyme activities are more important in the small intestine where bacterial densities are lower and the villi and microvilli increase the area of exposure. 

Studies on rats had shown no toxicity of astaxanthin preparations. Dietary administration of astaxanthin has proved to significantly inhibit carcinogenesis in the mouse urinary bladder, rat oral cavity, and rat colon. In addition, it is reported to induce xenobiotic-metabolizing enzymes in rat liver. 

Donnarumma L, G de Angelis, F Gramenzi, L Vittozzi (1988) Xenobiotic metabolizing enzyme systems in test fish. III. Comparative studies of liver cytosolic glutathione S-transferases. Ecotoxicol Environ Saf 16 180-186. 

The liver was the first organ in the gastrointestinal tract in which the role of ROMs in liver injury was established. Mitchell et al. (1973a, 1973b) demonstrated the roles of several drug-metabolizing enzymes in the formation of... 

Gradelet, S., P. Astorg, J. Leclerc et al. 1996. Effects of canthaxanthin, astaxanthin, lycopene and lutein on liver xenobiotic-metabolizing enzymes in the rat. Xenobiotica 26(1)49-63. 

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

The enterocyte expresses many of the metabolic enzymes that are expressed in the liver. These include UDP-glucuronyltransferases, sulfotransferases, esterases and cytochromes P450. 

From the above, it is clear that the gut wall represents more than just a physical barrier to oral drug absorption. In addition to the requirement to permeate the membrane of the enterocyte, the drug must avoid metabolism by the enzymes present in the gut wall cell as well as counter-absorptive efflux by transport proteins in the gut wall cell membrane. Metabolic enzymes expressed by the enterocyte include the cytochrome P450, glucuronyltransferases, sulfotransferases and esterases. The levels of expression of these enzymes in the small intestine can approach that of the liver. The most well-studied efflux transporter expressed by the enterocyte is P-gp. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

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