Basal clearance

First, it has been pointed out that the XC/MlP-receptor-deficient mice are reminiscent of cattle (and humans) deficient in leukocyte adhesion molecules. These animals do not react to normal pathogens with an innate immune response because the PMNs cannot locomote. Leukocytosis and myeloid expansion of the marrow and extramedullary hematopoiesis are observed. Presumably, lack of basal clearance of environmental flora by chemokine-driven leukocyte trafficking results in enhanced levels of growth factors that stimulate myelopoiesis, such as colony-stimulating factors. Lack of clearance may also contribute to the development of acquired immune responses such as the development of antibodies. 

It is also important to predict the in vivo biliary excretion clearance in humans, and for this purpose MDCK II cell lines expressing both uptake and efflux transporters may be used (Fig. 12.3) [92, 93]. It has been shown that MRP2 is expressed on the apical membrane, whereas OATP2 and 8 are expressed on the basolateral membrane after cDNA transfection (Fig. 12.3) [92, 93]. The transcellular transport across such double-transfected cells may correspond to the excretion of ligands from blood into bile across hepatocytes. Indeed, the vectorial transport from the basal to apical side was observed for pravastatin only in OATP2- and MRP2-expressing... 

Figure 5. Doses averaged over all epithelial cells in the bronchial and alveolar regions of the lung per unit exposure to potential alpha-energy as a function of aerosol size, compared with doses to basal cells for several models of airway size and clearance behaviour.

Exposure of various invertebrate species to high concentrations of petroleum did not induce mixed function oxidase activity. Enzyme activity was stimulated, however, in a number of fish tissues by petroleum. Different permutations can be addressed as to the significance of basal or induced levels of mixed function oxidases and hydrocarbon toxicity. AHH may have a physiological role in enhancing hydrocarbon clearance but may also increase the mutagenic-carcinogenic potential of hydrocarbons. Both of these concepts have been demonstrated in studies with fish (29,30). Induced AHH levels may permit a more rapid oxidative transformation with concomitant "disappearance" of parent hydrocarbons, but potentially toxic metabolites could be retained in tissues for longer periods (31). It is likely that at the enzymic level the... 

The central distribution of THC was studied in the primate brain using positron emission tomography (Charlambous et al. 1991). The THC analog, (-)-18F-A8-THC, was administered intravenously to baboons. Neuroanatomical distribution in the baboon brain was comparable to prior autoradiographic studies, with binding evident in the basal ganglia, thalamus, and cerebellum. Clearance was rapid from these areas. 

A number of parameters such as, e.g., renal clearance, basal oxygen consumption (metabolic rate), area under the curve (AUC), maximum metabolic velocity, or cardiac output correlate to the body weight to the power of 0.75 Further support for the power of 0.75 comes from a more... 

Figure 6 Directional transport of pravastatin in Oatplb2/Mrp2 double transfectants in the apical direction (A), and comparison of in vivo biliary excretion clearance and in vitro transcellular transport clearance across the double transfectant (B). (A) Transcellular transport across the monolayers of MDCK II cells was determined in the basal-to-apical and the opposite direction. (B) The x axis represents CLint determined in vitro multiplied by /B and the scaling factor, and the y axis represents the in vivo biliary clearance defined for the blood ligand concentrations. The symbol ( ) represents data whose x axis values were corrected for the scaling factor (a = 17.9). The solid line represents the theoretical curve, and the symbol (o), the observed data. Source From Ref. 59.

If Fa is known, Fgm can be estimated from AUCpo and AUCIV on the basis of Eq. (15). For most drugs that are readily released from the oral formulation and have high intestinal permeability, Fa is often assumed to be unity. The assumption that intestinal mucosa does not contribute to systemic clearance (i.e., negligible access of drug in systemic circulation to the intestinal mucosa) may be true under basal conditions, but might be inappropriate after treatment with the inducer, particularly if the inducer exerts a more profound effect on the gut wall enzyme compared with hepatic enzyme. Ignoring a possible contribution of the intestinal... 

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