Biotransformation rate determination

Although UGTs catalyze only glucuronic acid conjugation, CYPs catalyze a variety of oxidative reactions. Oxidative biotransformations include aromatic and side chain hydroxylation, N-, O-, S-dealkylation, N-oxidation, sulfoxidation, N-hydroxylation, deamination, dehalogenation and desulfation. The majority of these reactions require the formation of radical species this is usually the rate-determining step for the reactivity process [28]. Hence, reactivity contributions are computed for CYPs, but a different computation is performed with the UGT enzyme (as described in Section 12.4.2). 

In many cases, metabolism of a drug results in its conversion to compounds that have little or no pharmacologic activity. In such cases, biotransformation rate can be a primary factor determining the duration of drug action. 

Aquatic vascular plants and macroalgae can take up TNT dissolved in water very efficiently as indicated by removal rates determined for several species [11,12] some of which are promoted for use in phyto-treatment of explosives-contaminated water [11]. Less efficient removal of dissolved RDX was reported for wetland and aquatic plants [13,14], Efficient biotransformation and elimination mechanisms in aquatic vascular plants and macroalgae resulted in a lack of bioconcentration of TNT and its solvent-extractable transformation products [11,12], This chapter summarizes and discusses the bioconcentration, bioaccumulation, biotransformation, and toxicoki-netic processes of explosives in aquatic organisms. 

D. Determinants of Biotransformation Rate The rate of biotransformation of a drug may vary markedly among different individuals. This variation is most often due to genetic or drug-induced differences. For a few drugs, age or disease-related differences in drug metabolism are... 

For a number of reasons, there are some important limitations to the extension of this principle. Biodegradation—as opposed to biotransformation—of complex molecules necessarily involves a number of sequential reactions each of whose rates may be determined by complex regulatory mechanisms. For novel compounds containing structural entities that have not been previously investigated, the level of prediction is necessarily limited by lack of the relevant data. Too Olympian a view of the problem of rates should not, however, be adopted. An overly critical attitude should not be allowed to pervade the discussions—provided that the limitations of the procedures that are used are clearly appreciated and set forth. In view of the great practical importance of quantitative estimates of persistence to microbial attack, any procedure—even if it provides merely orders of magnitude—should not be neglected. 

Table 3 shows that the first-order rate constants for parent AHTN and HHCB biotransformation, determined by Federle et al. [ 12] and Artola-Garicano et al. 

The elimination rate of a compound (directly or by biotransformation) from an organism determines the extent of the bioconcentration and depends both on the chemical and the organism. Direct elimination includes transport across the skin or respiratory surfaces, secretion in gall bladder bile, and excretion from the kidney in urine. Other processes are moulting (for arthropods), egg deposition (fish, invertebrates) and transfer to offspring or via lactation (in mammals), which are more specific and not usually contemplated in bioconcentration determination. 

Most often, the rates for feedstock destruction in anaerobic digestion systems are based upon biogas production or reduction of total solids (TS) or volatile solids (VS) added to the system. Available data for analyses conducted on the specific polymers in the anaerobic digester feed are summarized in Table II. The information indicates a rapid rate of hydrolysis for hemicellulose and lipids. The rates and extent of cellulose degradation vary dramatically and are different with respect to the MSW feedstock based on the source and processing of the paper and cardboard products (42). Rates for protein hydrolysis are particularly difficult to accurately determine due the biotransformation of feed protein into microbial biomass, which is representative of protein in the effluent of the anaerobic digestion system. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

The rate of biotransformation of a chemical depends on the amount and efficiency of the pertinent biotransformation enzymes. Enzyme activity is partly genetically determined but may also vary between and within people because of enzyme induction caused by previous exposure to the same or related chemicals. Variation in enzyme activity may also be caused by enzyme inhibition due to concurrent exposures. 

Once a chemical enters the body of an animal (based on the route of entry), the chemical is subjected to metabolism by a variety of mechanisms. The toxicity of many chemicals is dependent on the metabolic rate and pattern of the system. Many tissues are capable of metabolizing substances. However, the maximum activities have been found to occur in the liver, followed by the lung, the intestine, the skin, and the kidneys. The nature of the chemical interactions, biochemical interactions, and metabolic transformations help to determine the toxicity of the chemical. A number of authors have written reviews about the biotransformation of many substances.19,25 28... 

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