Active drugs oxidative reactions

Fig. 8.14. Stepwise activation of dihydrotrigonelline-based chemical delivery systems, first by oxidation to a pyridinium cation (Reaction a), and then by hydrolysis to trigonelline and the drug ROH (Reaction b). Direct hydrolysis (Reaction c) is slow in comparison to the Reactions...

On the basis of the reactions and the biological activity of their products, the metabolism of drugs can be conveniently regarded as occurring in two phases (Wll). Phase one reactions consist of oxidation, reduction, or hydrolysis, and these result in (1) deactivation, (2) activation of an inactive compound into an active drug, (3) conversion of one active drug into another. 

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. 

Antioxidants are very effective in stabilizing products undergoing a free-radical mediated chain reaction. These products possess lower oxidation potentials than the active drug. Ideally, antioxidants are stable over a wide pH range and remain soluble in the oxidized form, colorless, and nontoxic. A listing of commonly used antioxidants can be found in Table 3. 

With the hypolipidemic drug-inducible cytochromes P-450 (CYP4A), there is transcriptional activation within 1 hour of administration of clofibrate. The levels of CYP4A1 are very low in the liver and kidney, but are markedly increased by the inducers. As well as cytochromes P-450, a number of other enzymes involved in peroxisomal p-oxidation reactions are also induced. 

The system protecting organisms from free radical excess comprises enzymes with oxide reductive activity, non-enzyme proteins, polypeptides, water and oil-soluble vitamins, SH-containing amino acids, flavonoids, carotinoids, etc. [40], Most of these compounds prevent oxidative stress evolution by interrupting chain oxidative reactions. That is why these substances are called substances with antiradical activity as well as antioxidants (AO). Foodstuff, nutrients and some drugs are sources of most antioxidants. 

Closures are composed of a polymer and include curing agents, activators, anti-oxidants, plasticizers, fillers and pigments within their formulae. They have to be selected with the drug product in mind to avoid chemical incompatibility and possible reaction with the ingredients in the product formulation. Sorption of the preservative from multiple-dose formulations has frequently been a problem and therefore closures may require saturation with the ingredients in the product prior to packaging. 

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