Drug metabolism

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 inhibiton 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.

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.

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.

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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 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.

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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 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.

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Drug-metabolising CYP450 enzymes

Cytochrome P450 enzymes are the main xenobiotic inactivators in humans.

The main families of CYP450 enzymes involved in drug metabolism are the monooxygenases of the CYP1, CYP2 and CYP3 families.

Prescribers need to be aware of drug interactions with any of these enzymes that may alter responses to any other prescribed medications.

In a novel approach, recent research is suggesting that it may be possible to harness the CYP450-inactivating capacity of some clinically-approved drugs to manage CYP450 catalyzed metabolism of arachidonic acid (AA), to reduce pathological conditions associated with elevated levels of certain AA metabolites (namely epoxyeicosatrienoic acids [EETs] and hydroxyeicosatetraenoic acids [HETEs]). This strategy is discussed by El-Sherbeni and El-Kadi (2016): Repurposing Resveratrol and Fluconazole to Modulate Human Cytochrome P450-Mediated Arachidonic Acid Metabolism.

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.

Average: 5 (1 vote)