Phase I oxidation, reduction, and

Foreign compounds may be metabolized by non-microsomal enzyme systems. These reactions include deamination of amines, oxidation of alcohols and aldehydes, reduction of aldehydes and ketones, hydrolysis of some esters and amides and may occur in the mitochondria, or the cell supernatant fraction, or in the circulating plasma. A thorough discussion of these non-microsomal mechanisms has been presented by Parke [20], These reactions are confined to Phase I oxidations, reductions, and hydrolyses (see Fig. 1). 

In both reactions, electron transfer induces the dissolution of the solid phase i.e., reductive and oxidative dissolution, respectively. Although no kinetic implications follow directly from the thermodynamic considerations, there are cases where the redox rate is related to the redox equilibrium (see e.g., Eq. 9.12). 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

Phase I reactions are typically divided into three categories oxidation, reduction, and... 

PHASE I METABOLISM Oxidations, reductions, and hydrolyses catalyzed by monooxygenases. 

Over the years, research efforts in biomedical sciences from academia, industry, and government institutions have underpinned a wealth of detailed knowledge regarding metabolism and physiology in humans and vertebrates, and many TK models have been developed. A critical aspect for the development of such models is the identification of the specific enzymes involved in the metabolism of a particular compound. For vertebrates these enzymes are well characterized, at least in terms of structure, if not also in terms of function, but such detailed knowledge is not available for invertebrates. In humans, metabolic routes can be split into phase I, phase II, and renal excretion. However, the relatively recent characterization of transporters such as P-glycoprotein has introduced them in the system as phase 0 or phase III because they can transport the parent compound or the metabolite. Major metabolic routes include phase I enzymes responsible for initial oxidation, reduction, and hydrolysis... 

A number of enzyme systems have evolved in animals and plants which effectively convert lipophilic xenobiotics to more polar compounds that are efficiently excreted. Phase I enzymes, responsible for oxidation, reduction, and/or hydrolysis, are integrated with phase II or conjugation enzymes for reactions of both types and are normally required for the formation of products polar enough to be readily excreted. The intracellular level of these enzymes, and thus, the capacity for biotransformation, increases in a coordinate fashion in response to exposure to xenobiotic compounds. This response is... 

Foreign compounds absorbed by mammals are subject to a variety of metabolic processes including functionalization and conjugation, also known as Phase I and Phase II metabolism, respectively. Common Phase I transformations indude oxidation, reduction, and hydrolysis while Phase II metabolism involves the biosynthesis of polar adducts (1). In general the metabolites of foreign compounds are more difficult to identify and quantitate than their parent structures due to their polarity and lower volatility. 

The process of xenobiotic metabolism contains two phases commonly known as Phase I and Phase II. The major reactions included in Phase I are oxidation, reduction, and hydrolysis, as shown in Figure 10.1. Among the representative oxidation reactions are hydroxylation, dealkylation, deamination, and sulfoxide formation, whereas reduction reactions include azo reduction and addition of hydrogen. Such reactions as splitting of ester and amide bonds are common in hydrolysis. During Phase I, a chemical may acquire a reaction group such as OH, NH2, COOH, or SH. 

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