Drug metabolism

The primary objective of drug metabolism is to facilitate a drug’s excretion by increasing its water solubility (hydrophilicity).

The involved chemical modifications incidentally decrease or increase a drug’s pharmacological activity and/or half-life, the most extreme example being the metabolic activation of inactive prodrugs into active drugs, e.g. of codeine into morphine by CYP2D6. The principal organs of drug metabolism are the liver and (for orally taken drugs) the small intestine. Drugs completely inactivated during the first-pass through these organs must be given parenterally, similarly to poorly absorbed drugs.

Hepato-intestinal drug metabolism is highly variable not only among patients but even in one particular individual over time. It is lower immediately after birth, in carriers of inactivating mutations in drug metabolizing enzymes, in patients treated with drugs inhibiting these enzymes (e.g. macrolids and conazols), and in those with liver disease or insufficient hepatic blood flow. It is higher in patients treated with transcriptional inducers of drug metabolizing enzymes, e.g. with rifampin or carbamazepine and, in the case of CYP2D6, in the presence of additional gene copies. The induction and inhibition of drug metabolism constitute examples of pharmacokinetic drug interactions. As drug metabolizing enzymes also metabolize certain endobiotics, induction and inhibition may result in metabolic disorders.  

Drug metabolizing enzymes have evolved primarily as a defense against non-medical chemicals taken up from the environment. They are therefore expressed also at other interfaces of the body with the environment such as the skin, lungs, and the kidney. The contribution of these organs to drug metabolism is incompletely understood, but certainly much smaller.

The principal effectors of drug metabolism are the cytochrome P450 (CYP450) enzymes.

The usual classification of drug metabolism enzymes and reactions as Phase I or II is somewhat misleading, as these reactions affect some drugs in a reverse order (Phase II followed by Phase I, e.g. isoniazid) or separately (Phase I or Phase II). Type I and II would be therefore more appropriate. Note that some drugs (e.g. metformin) are not metabolized at all.   

The most important difference between Phase I and II reactions is that the former one is molecule-autonomous whereas the latter one creates a covalent bond with another molecule or its part. Further, unlike Phase I, Phase II reactions almost invariably inactivate a given drug.

Most Phase I reactions are carried out by just several wide-spectrum monooxygenases of the CYP (cytochrome P450) subfamilies 1-3. The most important drug metabolizing enzyme is CYP3A4. Phase I reactions usually convert the parent drug to a more polar metabolite via the formation of –OH, -NH2, or –SH groups. Insufficiently polar drugs may be subsequently (or primarily) modified by Phase II enzymes. Phase I modifications may facilitate Phase II reactions. The most frequent Phase II reactions are conjugations with glucuronic acid. Drugs can be also conjugated with glutathione or glycine, or modified by the transfer of methyl, acetyl, or sulpha groups from donor compounds.


This article was published on