Phases of drug metabolism
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.
The Liver and Drug Metabolism
This is a short interactive teaching resource provided by the University of Nottingham for their nursing and midwifery students. It guides the user easily through the drug metabolism process.
Clinically relevant CYP450 substrates, inhibitors and inducers.
This webpage produced by Indiana University Department of Medicine lists clinically relevant CYP450 enzyme substrate drugs, and drugs which either inhibit or induce CYP450 activities, tabulated against the corresponding enzyme subtype.
This web page provides a brief overview of the drug metabolism process, rate of metabolism, the cytochrome P450 enzymes of Phase I reactions and the effects of Phase II conjugation reactions. The information was written by Jennifer Le, PharmD, MAS, BCPS-ID.