Metabolic activation factors influencing

Investigation of the differences in crystal packing between (431) and (426) from comparison of their respective X-ray structures, revealed that (431) was more tightly packed than (442), reflected in their respective melting points of 235 and 170 °C. It was postulated that the absence of in vivo activity for (431) may be explained by the resultant reduction in water solubility and dissolution rate compared with (426). The comparatively high calculated polar surface area of (431) (122.5A ) compared with (426) (89.3 A ) was also proposed as a factor influencing the marked difference in bioavailability between the two related compounds. Compound (426) (SLV-319) is currently being developed with Bristol-Myers Squibb for the potential treatment of obesity and other metabolic disorders. Phase I trials for obesity were started in April 2004. Earlier Phase I clinical trials for the treatment of schizophrenia and psychosis, which commenced in April 2002, appear to have been abandoned. 

Chemical carcinogenesis by polycyclic aromatic hydrocarbons (PAHs) is a multi-step process in which each of the steps must occur if a neoplasm is to develop. Thus, exposure to PAHs alone is not necessarily sufficient for the induction of a tumor. Many of these factors are summarized below and are discussed in various chapters of this volume. Considered here will be those factors influencing the reactions of the metabolically activated forms of the PAHs with DNA and the ways in which adducts may be detected and characterized. 

Several studies have been carried out to investigate the effect of pH on azo dye decolorization. In these assays, the decrease of absorbance at the wavelength corresponding to the maximum absorption for each dye is used as the method to evaluate the effectiveness of decolorization. Unfortunately, in most cases it is not clear if the isosbestic point of each dye was taken into account, and so it cannot be well understood if the different decolorization rate at different pH is due to a physical factor or to a differently influenced metabolic activity. 

It has beat proposed that possible mechanisms underlying the neuroprotective and/or neurotrophic properties of EGb in the CNS indude influences on neurotransmitters, energy metabolism and membrane functions, as well as antioxidant activities and inhibition of platelet-activation factor (PAF). 

Xenobiotics are biotransformed by phase I enzymes and phase II conjugation reactions to form a variety of metabolites that are generally more water-soluble and less toxic than the parent compound. Occasionally, the enzymic action of phase I or II systems leads to the formation of unstable intermediates or reactive metabolites that are toxic or carcinogenic. Many physiological factors influence the rate of xenobiotic metabolism and the relative importance of different pathways of metabolic activation or detoxication. 

Environmental conditions related to rock surface exposure have profound effects on biofilm development, as metabolic activity and growth are directly connected to the availability of water, energy sources and nutrients, as well as to conditions of temperature and irradiation. Another important factor for establishment of subaerial biofilms is the resistance of the supporting substrate to environmentally and biologically influenced disintegration and dissolution (wear-down). Rapidly weathering rock surfaces (e.g. porous sandstone in an intertidal coastal zone) show little or... 

Several factors influence the toxicity of substances their structure and innate chemical activity, the dosage, the susceptibility, age and sex of specific organisms, the route of exposure, susceptibility of the substances to being absorbed, the way in which they spread within the receiving organism, their metabolism and excretion, and the presence of other chemicals or conditions. 

In many cases, multiple biochemical pathways are activated by the intake of therapeutical drugs. The activation of side mechanisms coincides with the consequent side effects. This concept has led to research areas like polypharmacology as well as re-purposing studies. In such cases, the possibility of activating of multiple biochemical pathways is employed to explore alternative therapeutic uses of the same compound. In addition to the ligand-receptor process, it is necessary to take into consideration the other mechanistic features that might also be involved and affect the analysis, such as the metabolism, transport based on carry proteins, co-factors, influence of metals, etc. 

A variety of genetic, physiological and pathological factors influence xenobiotic metabolism and hence the wanted and unwanted activities associated with a drug. In this very brief section, we restrict ourselves to a conceptual overview and invite readers to personal... 

---