Drug Metabolism

Drug metabolism occurs in many sites in the body, including the liver, intestinal wall, lungs, kidneys, and plasma.

As the primary site of drug metabolism, the liver functions to detoxify and facilitate excretion of xenobiotics (foreign drugs or chemicals) by enzymatically converting lipid-soluble compounds to more water-soluble compounds.


  1. Phase I Drug metabolism consists of phase I reactions such as oxidation, hydrolysis and reduction,

  2. Phase II reactions: which primarily involve conjugation of the drug with substances such as glucuronic acid and sulphuric acid.

Phase I Reactions:

Phase I metabolism generally involves the cytochrome P450 (CYP450) mixed function oxidase system

Introduction to CYP 450

Cytochrome P450 (CYP) is a hemeprotein that plays a key role in the metabolism of drugs and other xenobiotics.

The liver is the major site of cytochrome 450-mediated metabolism, but the enterocytes in the small intestinal epithelium are also potentially important.

CYP450 isoenzymes: The CYP450 system comprises 57 isoenzymes, each derived from the expression of an individual gene.

Classification for nomenclature

  • family number

  • a subfamily letter and

  • a number for an individual enzyme within the subfamily (Wilkinson, 2005).

Four main subfamilies of P450 isoenzymes are thought to be responsible for most (about 90%) of the metabolism of commonly used drugs in humans: CYP1, CYP2, CYP3 and CYP4.

Mostly studied CYP450 enzyme:

The most extensively studied isoenzyme is CYP2D6, also known as debrisoquine hydroxylase.

Common Enzymes:

Of the many isoenzymes, a few (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) appear to be responsible for the human metabolism of most commonly used drugs.


The genes that encode specific cytochrome 450 isoenzymes can vary between individuals and, sometimes, ethnic groups. These variations (polymorphisms) may affect metabolism of substrate drugs. It shows a polymodal distribution and people may be described according to their ability to metabolise debrisoquine. Poor metabolisers tend to have reduced first-pass metabolism, increased plasma levels and exaggerated pharmacological response to this drug, resulting in postural hypotension. By contrast, ultra-rapid metabolisers may require considerably higher doses for a standard effect. About 5–10% of white Caucasians and up to 2% of Asians and black people are poor metabolisers.

CYP3A4 and CYP3A5

The CYP3A family of P450 enzymes comprises two isoenzymes, CYP3A4 and CYP3A5, so similar that they cannot be easily distinguished. CYP3A is probably the most important of all drug-metabolising enzymes because it is abundant in both the intestinal epithelium and the liver and it has the ability to metabolise a multitude of chemically unrelated drugs from almost every drug class. It is likely that CYP3A is involved in the metabolism of more than half the therapeutic agents that undergo alteration by oxidation. In contrast to other cytochrome 450 enzymes, CYP3A shows continuous unimodal distribution, suggesting that genetic factors play a minor role in its regulation. Nevertheless, the activity of the enzyme can vary markedly among members of a given population.

Substrates for Cytochrome:

Substrates are numerous and diverse compounds.

  • Endogenous – cholesterol, steroid hormones, and fatty acids.

  • Exogenous – drugs, food additives, and environmental contaminants (ex. cigarette smoke).

Biological functions

  • Production of steroid hormones, vitamins A and D, lipid-like eicosanoid molecules involved in signaling

  • Metabolism of fatty acids and eicosanoids } e.g. P450 CYP51, essential in eukaryotic sterol biosynthesis.

  • Detoxification

  • Many substrates are lipid-soluble; hydroxylation increases solubility


Characteristic absorbance at 450 nm when cyanide is bound.


The effect of a cytochrome 450 isoenzyme on a particular substrate can be altered by interaction with other drugs. Drugs may be themselves substrates for a cytochrome 450 isoenzyme and/or may inhibit or induce the isoenzyme. Inhibition or induction of a single isoenzyme would have little effect on plasma levels of the drug. However, if a drug is metabolised primarily by a single cytochrome 450 isoenzyme, inhibition or induction of this enzyme would have a major effect on the plasma concentrations of the drug.

Enzyme induction.

The most powerful enzyme inducers in clinical use are the antibiotic rifampicin and antiepileptic agents such as barbiturates, phenytoin and carbamazepine. Some enzyme inducers, notably barbiturates and carbamazepine, can induce their own metabolism (autoinduction).

Enzyme-inducing drugs with short half-lives such as rifampicin will induce metabolism more rapidly than inducers with longer half-lives, for example, phenytoin, because they reach steady-state concentrations more rapidly.

Enzyme inhibition.

Enzyme inhibition is responsible for many clinically significant interactions. Many drugs act as inhibitors of cytochrome 450 enzymes

  1. A strong inhibitor is one that can cause ≥5-fold increase in the plasma area-under-the-curve (AUC) value or more than 80% decrease in clearance of CYP3A substrates.

  2. A moderate inhibitor is one that can cause ≥2- but <5-fold increase in the AUC value or 50–80% decrease in clearance of sensitive CYP3A substrates.

  3. A weak inhibitor is one that can cause ≥1.25- but <2-fold increase in the AUC values or 20–50% decrease in clearance of sensitive CYP3A substrates when the inhibitor is given at the highest approved dose and the shortest dosing interval.


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