Biotransformation reactions affecting drugs (as well as other xenobiotics) are traditionally separated (or, conveniently divided) into Phase I and Phase II reactions. The reactions of Phase I are thought to act as a preparation of the drug for  phase  “functionalises” the parent drug molecule by producing or uncovering a chemically reactive group on which the phase II reactions can occur. For example, a –CH3 moiety can be functionalized to become a –CH2OH or even a –COOH group. Through introduction of oxygen into the molecule or following hydrolysis of esters or amides, the resulting metabolites are usually more polar (subsequently, less lipid-soluble) than the parent drug, therefore presenting reduced ability to penetrate tissues and less renal tubular resorption than the parent drug. These primary metabolites are then further converted to secondary metabolites, involving a process of conjugation of an endogenous molecule or fragment to the substrate, yielding a metabolite known as a conjugate. Conjugates are usually more hydrophilic than the parent compound, and subsequently much more easily excreted via the kidney.

There is a third class of metabolites, recognized as xenobioticmacromolecule adducts (also called macromolecular conjugates), formed when a xenobiotic binds covalently to a biological macromolecule. As a very recent example of sequential metabolism, we mention that of 2,3,7-trichlorodibenzo-p-dioxin (2,3,7-triCDD) by cytochrome P450 and UDP-glucuronosyltransferase in human liver microsomes. This study investigated the glucuronidation of 2,3,7-triCDD by rat CYP1A1 and human UGT. The ability of ten human liver microsomes to metabolise this polychlorinated compound was assessed. As another representative example of sequential metabolism, we present the biotransformation of propranolol, a process that leads to two metabolites, Propranolol is first oxidised to 4- hydroxypropranolol, which then undergoes sequential metabolism to 4-hydroxypropranolol glucuronide other biotransformation reactions of propranolol will be presented later another possibility, occurring frequently, is that of parallel metabolism leading to a common metabolite.

We give as a representative example of parallel metabolism, the biotransformation of dextromethorphan via two CYTP450 isoforms; both pathways involve N- and O-demethylation steps, but in reverse order, leading to a common metabolite Reversible metabolism may occur when a metabolite or biotransformation product and the parent drug undergo interconversion. Although reversible metabolism is less common, there are examples occurring across a variety of compounds, including phase I metabolic pathways (for some amines, corticosteroids, lactones and sulphides/sulphoxides), as well as phase II metabolic pathways (including reactions of glucuronidation, sulphation, acetylation etc.) A recently published, detailed account of the subject of reversible metabolism of drugs highlights the complexity of the pharmacokinetic treatment of such processes as well as the fact that two compounds undergoing metabolic interconversion may have different activities. Thus, for example, in the well-known prednisone-prednisolone system, both compounds are active but in the case of the reversible metabolism involving haloperidol and it metabolite, reduced haloperidol, the latter compound is an inactive and possibly toxic species. Clinical implications of this system are discussed in depth. Thus, an aspect worth stressing from the outset is that in the case of a xenobiotic having a single metabolite, the following scenarios present themselves.

Best Regards,
Nancy Ella
Editor-In-Charge
Drug Designing: Open Access