Drug Review

Cytochrome P450 Drug Metabolism

Editors: James V. Forgione PharmD, RPh; Dan Randall MD, MPH, FACP All Editors & Disclosures

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Background Information

Description

  • Cytochrome P450 (CYP) enzymes are considered the major enzyme family capable of catalyzing oxidative biotransformation (phase 1 metabolism) of most drugs and other lipophilic xenobiotics.,,
    • CYP enzymes are bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide.
    • Metabolism of a drug by CYP enzyme is a major source of variability in drug pharmacokinetics and patient response to treatment.
    • Of at least 57 functional human CYPs, approximately 12 enzymes (in the CYP1, 2, and 3 families) are responsible for the biotransformation of most commonly used drugs and foreign substances (xenobiotics).
    • These CYP enzymes affect the metabolism of 70%-80% of all drugs in clinical use.
  • CYPs are predominantly expressed in the liver, but can also occur in the small intestine (where they may reduce drug bioavailability), lungs, placenta, and kidneys.
  • Major cytochrome phase 1 metabolic pathways:,
    • Cytochrome enzymes catalyze oxidation and reduction.
      • They may decrease activity, such as by making substrates more water soluble for excretion by the kidneys. Also, cytochrome enzymes may convert substrates into their active form (prodrug converts to active drug.
    • Examples of metabolic pathways affected by CYPs include hydroxylation, demethylation, dealkylation, and deisopropylation.
  • FDA has required an evaluation and reporting of CYP450 metabolism and its potential for inhibition or induction of every drug approved since 1997.

Definitions

  • Substrates are drugs or other substances (xenobiotics) which are metabolized by cytochrome enzymes. These include:
    • Pharmacologically active drugs which require metabolism to its inactive form for clearance from the body
    • Metabolically activated drugs (prodrugs) which require conversion to the active form of the drug
  • Inhibitors are substances which compete with other drugs for ≥ 1 CYP enzyme, affecting the therapeutic response to that medication.,
    • Inhibitors will decrease clearance of substrates requiring biotransformation for excretion, and may lead to an enhanced effect or toxic levels of the substrate.
    • Inhibitors may reduce the effect of substrates (prodrugs) which require conversion into an active drug in the body.
  • Inducers are substances which increase CYP enzyme activity by increasing enzyme synthesis.
    • Due to the length of time required for the body to synthesize enzymes, full development of the enzyme induction interaction may take days or weeks.
    • Interactions may be slow to resolve depending on the duration enzymes are in the body (the half-life).

Cytochrome P450 Classification

  • Cytochrome P450 (CYP) enzymes have been subdivided into families and subfamilies according to amino acid structure similarity:
    • Enzymes with > 40% amino acid sequence similarity are grouped into families denoted with number (for example, CYP1, CYP2, and CYP3).
    • Enzymes with > 55% amino acid sequence similarity are grouped into subfamilies designated by a letter (for example CYP2C, CYP2D, and CYP2E).
    • Individual isoenzymes are further identified by a number (for example CYP2D6).
  • CYP enzymes activity may also be quantified by:
    • Magnitude of the effect of an inducer or inhibitor on a substrate (weak, moderate, or potent)
    • Specificity of a substrate for a particular isoenzyme (minor, moderate, or sensitive)
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DynaMed Levels of Evidence

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DynaMed provides easy-to-interpret Level of Evidence labels so users can quickly find and determine the quality of the best available evidence. Evidence may be labeled in one of three levels:

1Level 1 (likely reliable) Evidence
Representing research results addressing clinical outcomes and meeting an extensive set of quality criteria which minimizes bias.
There are two types of conclusions which can earn a Level 1 label: levels of evidence for conclusions derived from individual studies and levels of evidence for conclusions regarding a body of evidence.
2Level 2 (mid-level) Evidence
Representing research results addressing clinical outcomes, and using some method of scientific investigation, but not meeting the quality criteria to achieve Level 1 evidence labeling.
3Level 3 (lacking direct) Evidence
Representing reports that are not based on scientific analysis of clinical outcomes. Examples include case series, case reports, expert opinion, and conclusions extrapolated indirectly from scientific studies.

Grades of Recommendation

Guideline producers are now frequently using classification approaches for their evidence and recommendations, and these classifications are recognized and requested by guideline users. When summarizing guideline recommendations for DynaMed users, the DynaMed Editors are using the guideline-specific classifications and providing guideline classification approach when this is done.

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