Lumenal metabolism

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... 

Lumenal metabolism. This may be triggered by digestive enzymes secreted from the pancreas (amylase, lipases, and peptidases including trypsin and a-chymotrypsin), and those derived... 

Cephalosporins. These drugs (e.g. cephaloridine) may be nephrotoxic causing proximal tubular necrosis. The drug accumulates in the kidney as a result of active uptake following active secretion into the tubular lumen. Metabolic activation via cytochrome P-450 may be involved. Glutathione is oxidized and as NADPH is also depleted, the GSSG cannot be reduced back to GSH. As vitamin E-depleted animals are more susceptible it has been suggested that lipid peroxidation may be involved. 

Figure 42-11. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (at bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (Tgb, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyro-sine Tj, triiodothyronine T4, tetraiodothyronine.) Asterisks indicate steps or processes that are inherited enzyme deficiencies which cause congenital goiter and often result in hypothyroidism.

In this model, no attempt is made to reproduce the in vivo physiochemical conditions occurring in the lumen of the human small intestine during digestion. This cell culture model only provides information about the intestinal absorption and metabolism processes of the compound. Using this cell culture system in con-... 

In situ perfusion studies assess absorption as lumenal clearance or membrane permeability and provide for isolation of solute transport at the level of the intestinal tissue. Controlled input of drug concentration, perfusion pH, osmolality, composition, and flow rate combined with intestinal region selection allow for separation of aqueous resistance and water transport effects on solute tissue permeation. This system provides for solute sampling from GI lumenal and plasma (mesenteric and systemic) compartments. A sensitive assay can separate metabolic from transport contributions. 

KF Ilett, LBG Tee, PT Reeves, RF Minchin. Metabolism of drugs and other xenobi-otics in the gut lumen and wall. Pharm Ther 46 67-93, 1990. 

Faigle, J. W., Drug metabolism in the colon wall and lumen, in Colonic Drug Absorption and Metabolism. 

It is contended that the renal slice technique measures primarily basolateral uptake of substrates or nephrotoxins, based on histological evidence of collapsed tubular lumens. This results in the inaccessibility of brush-border surfaces for reabsorptive transport (Burg and Orloff, 1969 Cohen and Kamm, 1976). This observation limits the ability of this model to accurately reflect reactions to nephrotoxins that occur as the result of brush-border accumulation of an injurious agent. Ultrastructurally, a number of alterations, particularly in the plasma membrane and mitochondrial compartments, have been shown to occur over a 2-h incubation period (Martel-Pelletier et al., 1977). This deterioration in morphology is very likely a consequence of the insufficient diffusion of oxygen, metabolic substrates, and waste products in the innermost regions of the kidney slice (Cohen and Kamm, 1976). Such factors also limit the use of slices in studying renal metabolism and transport functions. 

If a drag is substantially metabolized but it is reasonable to assume that metabolites are not produced in the gut lumen, urinary recovery of drag and metabolites might be a useful measure of absorption. 

In order for allelochemicals to enter the body of a herbivore, absorption must occur across the gut lining. Curtailing the initial absorption of dietary allelochemicals may be a herbivore s first line of defense against plant toxins. Studies have citied the lack of absorption or metabolism of lipophilic plant secondary metabolites (i.e., terpenes), conducive to phase I or II detoxification, in the gut of terrestrial herbivores rather these compounds are excreted unchanged in the feces (Marsh et al. 2006b). While physical barriers or surfactants have been used to explain this limited adsorption in both marine and terrestrial herbivores (Lehane 1997 Barbehenn and Martin 1998 Barbehenn 2001 for review of marine herbivores, see Targett and Arnold 2001), active efflux of plant allelochemicals out of enterocytes into the gut lumen has received limited attention until now. 

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