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Learn about Drug Metabolism

Drug Metabolism


Drug metabolism is incredibly important for the efficacy of a drug. Decreases in hepatic activity can result in increased blood concentration of said drug. This might result in an increased risk of drug toxicity or side effects. Counter to this, increased hepatic metabolism results in decreased blood concentration of a drug and decreased therapeutic effect.


Drug metabolism is largely controlled by the liver and involves three distinct phases. Phase I reactions add a functional group (for instance -OH or NH2), increase the polarity of the drug and provide a site for phase II reactions. Phase II reactions almost always result in the drug becoming physiologically inactive. The drug will also become more hydrophilic, making excretion (phase III) easier.



Metabolizing enzymes:


Phase I reactions usually involve adding a functional group. As such reductions, hydrolysis and oxidation are all common reactions. Some 75% of these are controlled by the Cytochrome P450 (or CYP) enzyme family. CYP enzymes are part of the heme cofactor superfamily and thus described as hemoproteins. Several hundred isoforms of P450 enzymes exist. These isoforms differ in amino acid sequence, resulting in differences in the molecules that regulate them (eg inhibit or induce) and in the reactions they catalyze.


CYP metabolism and CYP2D6 metabolism


As drug metabolism is so important for the efficacy of a given drug, we screen for polymorphisms in a number of CYP metabolizing enzymes. These include:


  • CYP2B6
  • CYP2C8
  • CYP2C9
  • CYP2C19
  • CYPD6
  • CYP4A4/CYP3A5


Taking CYPD6 as an example, the enzyme is involved in the metabolism of 25% of all clinically important medications. Hepatic enzyme CYP2D6 is clinically relevant because polymorphisms can interrupt the conversion of codeine to its active form, morphine. The gene encoding CYP2D6 has a differential expression in just over 1% of the population.


In a portion of this 1% CYP2D6 is a poor metabolizer of codeine. These individuals cannot convert codeine to morphine and gain no pain relief from the drug. They also exhibit exaggerated side effects of codeine as its blood concentration is higher for longer. Another polymorphism of CYP2D6 results in ultra rapid metabolism resulting in toxic levels of morphine. This is some in Table 1.



Genetic screening with
Rxight® means that these polymorphisms are identified before the individual suffers adverse side effects. Pain treatment is faster and more specific.


This is just one example of variability associated with a CYP2D6 assay. Other drugs metabolised by the enzyme include:


  • Desipramine
  • Imipramine
  • Amitriptyline
  • Haloperidol
  • Venlafaxine
  • Risperidone


Pharmacogenetic testing thus can provide a simple and effective way to reduce side effects and provide a more targeted therapy to patients.







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