Examples of Metabolite Structure Determination from Known Biotransformations

8 EXAMPLES OF METABOLITE STRUCTURE DETERMINATION FROM KNOWN BIOTRANSFORMATIONS 

The availability of the chemical structure and NMR assignment s for the parent compound, as illustrated in Section 12.7 for Buspirone, significantly simplifies the identification of related metabolites. A significant amount of information has already been accumulated and presented in the literature that describes numerous metabolic reactions associated with a variety of metabolic pathways. Examples of the most common metabolic reactions are tabulated in Table 12.11. These metabolic reactions identify a range of possible chemical modifications that may be applied to the parent compound and generate a variety of related metabolites. 

Occasionally, xenobiotics undergo metabolic activation to produce reactive intermediates, where these intermediates rearrange to form an unpredictable metabolite. For example, the metabolic activation of DPC 963 in rat formed a highly reactive oxirene intermediate (Chen et al., 2002). This intermediate rapidly rearranged to form an unstable cyclobutenyl ketone through possible intermediates a or b (Fig. 12.13). This reactive intermediate was prone to nucleophilic attack and in this case reacted with glutathione via a 1,4 Michael addition that resulted in two isomeric GSH adducts M3 and M4. The H NMR spectrum provided evidence in support of the M3 and M4 structures. First, both the aromatic hydrogens were still present in the metabolite. Second, the 

Proton and carbon chemical shifts of pholcodine and its A-oxide 

Protons Parent A-oxide AS Carbons Parent A-oxide AS 

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