Is the parent drug as well as its associated metabolites adequately evaluated for safety in preclinical studies? Dr Sean Kitson from Almac’s Radiolabelling and Biocatalysis Group gives an interpretation.
A xenobiotic (drug) entering the human body will undergo a series of biotransformations via phase I and phase II metabolic pathways.1 During phase I, enzymatic processes in the liver – such as cytochrome P450 – and other tissues will modify the chemical structure of the drug by introducing reactive or polar groups (hydroxyl, thiol, amino and carboxylic acid, for example). These biomodifications render the parent drug more water-soluble to allow the body to eliminate it more easily. The metabolites produced will have a similar chemical structure to the parent drug and may be more pharmacologically active at the therapeutic receptor sites.
In phase II, the drug is conjugated to produce a more water soluble and pharmacologically inactive metabolite. Phase II reactions can be catalysed by transferase enzymes, such as glutathione-S-transferases, with the conjugated metabolite usually exiting the body via a detoxification mechanism. Moreover, the majority of phase II reactions are catalysed by UDP glycosyltransferases.2
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