Mucosal metabolism

Hussain MA, Seetharam R, Wilk RR, Aungst BJ, Kettner CA (1995) Nasal mucosal metabolism and absorption of pentapeptide enkephalin analogs having varying N-terminal amino acids. J Pharm Sci 84 62-64. 

M. A. Hussain and B. J. Aungst. Nasal mucosal metabolism of an LH-RH fragment and inhibition with boroleucine. Int J Pharm 105 7-10 (1994). 

Many CYP3A substrates are also subject to efflux transport by P-gp at the intestinal mucosa (88-90). As discussed above, P-gp is inducible via activation of nuclear orphan receptors by the same inducers of CYP enzymes (91). Accordingly, for those drugs which are substrates of both CYP and P-gp, reduction in intestinal availability following treatment with known microsomal enzyme inducers could reflect the joint effects of increased mucosal metabolism and apical efflux. 

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. 

Iron is another vital nutrient in the development of functioning erythrocytes it is essential for the formation of hemoglobin. Lack of iron leads to a decrease in hemoglobin synthesis and ultimately red blood cells. Normal homeostasis of iron transport and metabolism is depicted in Fig. 63-2.7 Approximately 1 to 2 mg of iron is absorbed through the duodenum each day, and the same amount is lost via blood loss, desquamation of mucosal cells, or menstruation. 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

Mitomycin C is an alkylating agent that forms cross-links with DNA to inhibit DNA and RNA synthesis. The pharmacokinetics of mitomycin C are best described by a two-compartment model, with an a half-life of 8 minutes and a terminal half-life of 48 minutes.31 Liver metabolism is the primary route of elimination. Mitomycin C has shown clinical activity in the treatment of anal, bladder, cervix, gallbladder, esophageal, and stomach cancer. Side effects consist of myelosuppression and mucositis, and it is a vesicant. 

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

Solute uptake can also be evaluated in isolated cell suspensions, cell mono-layers, and enterocyte membrane vesicles. In these preparations, uptake is normalized by enzyme activity and/or protein concentration. While the isolation of cells in suspension preparations is an experimentally easy procedure, disruption of cell monolayers causes dedifferentiation and mucosal-to-serosal polarity is lost. While cell monolayers from culture have become a popular drug absorption screening tool, differences in drug metabolism and carrier-mediated absorption [70], export, and paracellular transport may be cell-type- and condition-depen-dent. 

JPF Bai, GL Amidon. Structural specificity of mucosal-cell transport and metabolism of peptide drugs. J Pharm Sci 9 969-978, 1992. 

Yeum, K. J., Y. C. Leekim et al. (1994). In vitro metabolism of beta-carotene by lipoxygenase and human stomach mucosal homogenates. FASEB J. 8(4) A192-A192. 

Fluxes of iron from the plasma towards BM and other tissues can be quantified by ferrokinetic studies, using 59Fe and sophisticated computer models (Ricketts et ah, 1975 Ricketts and Cavill, 1978 Barosi et ah, 1978 Stefanelli et ah, 1980). Plasma iron turnover (PIT), erythroid iron turnover (EIT), non-erythroid iron turnover (NEIT), marrow iron turnover (MIT), and tissue iron turnover (TIT) could be calculated in many disorders of iron metabolism and in all kinds of anaemias. Iron is rapidly cleared from the plasma in iron deficiency and in haemolytic anaemias. If more iron is needed for erythropoiesis, more transferrin receptors (TfR) are expressed on erythroblasts, resulting in an increased flux of iron from intestinal mucosal cells towards the plasma. In haemolytic anaemias MPS, and subsequently hepatocytes, are overloaded. In hereditary haemochromatosis too much iron is absorbed by an intrinsic defect of gut mucosal cells. As this iron is not needed for erythropoiesis,... 

Cartwright [124] reported that miconazole was slightly absorbed from epithelial and mucosal surface. The drug is well absorbed from the gastrointestinal tract, but caused nausea and vomiting in some patients. The drug may be given intravenously but was associated phlebitis. Up to 90% of the active compound was bound to plasma protein. Distribution into other body compartments was poor. Metabolism was primarily in the liver, and only metabolites were excreted in the urine. At therapeutic levels, they were relatively nontoxic both locally and systematically, but occasionally produced disturbances on the central nervous system. 

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