Drug biotransformation phase reactions

Two types of enzymatic pathways, the so-called phase I and phase II pathways, are generally implicated in drug biotransformation. Phase I pathways correspond to functionalization processes, whereas phase II correspond to biosynthetic or conjugative processes. Phase I functionalization processes include oxidation, reduction, hydrolysis, hydration, and isomerization reactions. 

Phase II drug biotransformation involves reaction (conjugation) of a range of functional groups with endogenous compounds (Table 1). The resultant... 

Table 3.2. Biotransformation of drugs by phase 1 and phase 2 reactions...

Phase II reactions are relatively faster than P450-catalyzed reactions, thus effectively accelerating drug biotransformation. 

The chemical reactions involved in drug biotransformation are also classified as either phase I or phase II reactions.27,28 52 60 Phase I reactions consist of those using oxidation, reduction, or hydrolysis. Phase II reactions involve conjugation of the parent drug or the metabolite of a drug that was already metabolized using a phase I reaction. 

Drug biotransformations may occur through one or both of phase I and phase II reactions (Table 6.2). Phase I reactions usually, but not always, precede phase II. 

Fig. 31.1 Sequential steps of drug biotransformation. After uptake by the cell, a phenyl ring of a xenobiotic undergoes first a functionalization reaction (oxidation, phase I). The hydroxyl metabolite is then conjugated by addition of a sulfate group (phase II), before being exported from the cell by transporters (phase III) and excreted. P-450, cytochromes P-450 ST, sulfotransferases.

Identification of metabolic reactions at an early phase can significantly affect the drug discovery process, because bioavailability, activity, toxicity, distribution and final elimination all depend on metabolic biotransformations [1], Once obtained, this information can help researchers judge whether or not a potential candidate should be eliminated from the pipeline or modified to reduce the affinity for CYP antitarget enzymes. 

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