Human metabolism characteristics

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Florea BI, Cassara ML, Junginger HE, Borchard G (2003) Drug transport and metabolism characteristics of the human airway epithelial cell line Calu-3. J Control Release 87(1-3) 131-138. 

Both Pu and Th will probably enter the skeleton and other internal tissues predominantly from inhalation. This statement is based on the fact that in the field, Pu and Th demonstrate similar transfers from soil to small mammals and laboratory studies demonstrate similar metabolic characteristics (1,3,23). Soil chemical behavior is also similar (20). As demonstrated in Table I, natural Th in human bone originates largely from inhalation, even assuming that adsorption from the diet is 0.1%. Another strong agrument for the importance of inhalation is found in tissue distributions of Th-232 and Th-230 in humans. Table V summarizes work by Wrenn, et al. (53) which shows that lungs of non-occupationally exposed individuals contains burdens of Th isotopes comparable to the skeleton. Thorium-228 distributions are different from Th-230,... 

Because clearance at the whole-body level often is determined by metabolism at the cellular level, it is possible to use a variety of human-derived in vitro systems to determine rates of metabolism. These systems include pure human enzymes (such as cytochrome P450 enzymes) (13) and human liver subcellular fractions (S9 and microsomes) (14). However, with enzymes and subcellular fractions, some information is lost because the whole-cell integration of subcellular processes has been disrupted. The use of cultured human hepatocytes retains the whole-cell integration at the expense of greater experimental complexity (15). Each system provides a different window on the metabolic processes, is relatively easy to use, and can be obtained from commercial sources. Rates and pathways of metabolism may be compared with a series of discovery compounds to identify those with the greatest relative metabolic stability or with a benchmark compound of known human PK characteristics to provide a more absolute estimate of hepatic metabolic clearance. 

The following review focuses on experimental data supporting different metabolic characteristics of 1,3-DAG or DAG oil containing 1,3-DAG (Table 2). Relevant areas of observed differences between 1,3-DAG/DAG oil and TAG/TAG oil metabolism include postprandial lipid metabolism and use of macronutrient fuels. Observations from animal and human experimental data are included. 

Besides the indoor air pollution caused by residential energy consumption, decorating and refurbishing materials, and building materials, indoor air pollutants also come from other sources, such as environmental tobacco smoking, products for household cleaning and maintenance, human metabolism, and outdoor contaminated air, as in any other country. See other chapters of this volume for discussions of the characteristics of indoor air pollution caused by these sources. 

The variations in human metabolic profiles can seldom permit visual observations of meaningful metabolic deviations from the normal. However, large computer systems do have the general capability to extract the distinct features from large data sets, and reduce the bulk of data from capillary GC of numerous patients to a more easily understandable form. Precisely measured retention characteristics and the peak areas form the basis for such comparisons. Pattern recognition methods have been utilized to classify diabetic samples [169,170] and those of virus-infected patients [171] with the aid of training sets from clinically defined cases. In addition, the feature extraction approach [169,170] permits identification of important metabolite peaks in complex chromatograms. 

The natural arsenolipids of fish oils, currently of unknown structure, show interesting transformations in humans, producing characteristic metabolites that offer some insight into the structures of the original lipid. The major metabolic products in the urine were dimethylarsinate and four fatty acids, oxo- and thio-DMAP and oxo- and thio-DMAB. It seems likely that the thio-arsenicals were formed from the oxo analogs in the body. These results suggest that the arsenic is incorporated into the lipid as a dimethylated moiety and may be present as a number of fatty acid derivatives. 

HORMONAL REGULATION OF HUMAN METABOLISM 7.2.1 General Characteristics of Human Metabolism... 

Dietary diacylglycerols (DAG) comprise a natural component of various edible oils and are consumed as food. The nutritional function of DAG, however, has not been studied until recently. Some research into the nutritional characteristics of dietary DAG has occurred, and our knowledge of its functions in humans and animals is accumulating. Through these studies, it was shown that DAG, particularly in the 1,3-isoform, have metabolic characteristics distinct from TAG, which may produce beneficial effects with regard to the prevention and management of postprandial lipidemia and obesity. 

Escherichia coli normally lives in intestinal tracts and, in particular, in the large intestine of human beings and warm-blooded animals. Outside the intestinal tract, it can only live for a short time in water and in the ground and therefore indicates relatively fresh faecal contamination. Thus, when Escherichia coli is present in water, one also has to reckon on the presence of pathogenic intestinal bacteria such as Salmonella, Shigella and cholera vibrios. Escherichia coli is easy to cultivate on culture mediums and can, by reason of its metabolic characteristics in the so-called... 

Structural evolution. In addition to having similar morphological features, lesions found in the colon of rodents and humans exhibit, to some degree, similar histochemical (Filipe, 1975), biochemical, and metabolic characteristics (Kim and McIntyre, 1983). 

The human metabolism of these sulphur compounds is complex and far from understood. Moreover, due to the complexity and number of potential products, it is difficult to generalize. Several compounds probably conjugate with glutathione post-absorption, and are metabolized via the mercapturic acid pathways, in a similar manner to isothiocyanates. N-acetyl-S-aUyl-L-cysteine (allylmercapturic acid), derived from diallyl disulphide, has been detected in urine from humans who have consumed garlic (de Rooji et al. 1996). The characteristic breath and perspiration odours foimd following garlic consumption are... 

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