M - Metabolism

This lesson is the fourth in the Pharmacokinetics series. It introduces Metabolism, the M in the four elements (ADME) of pharmacokinetics. This video introduces phase I metabolism (modification e.g. by CYP enzymes) and phase II metabolism (e.g. glucuronidation to permit excretion).

Next Lesson: Excretion 

Take Home Message:
Metabolism has multiple roles including modifying a pro-drug to its active form, and conjugating to permit excretion.

In 2003, a senior executive at GlaxoSmithKline received quite a lot of (bad) press for saying that "[many drugs] don't work on most people". One of the primary underlying causes is metabolic differences, which are often genetic in basis. Genetic variations in the cytochrome P450s are a well-known example.

The cytochrome P450 enzymes are key to phase I metabolism, and are known to have many variants which can significantly alter the required dose of a drug. e.g.:

  • CYP2D6 and Nortriptyline - Doses can vary between 10mg to >500mg (with the same effect!) depending on genotype and copy number.
  • CYP2C9 and Warfarin - Starting doses can vary between 1mg and 7mg.

In the second hands-on tutorial (to be posted), we will look at some real examples of patients with significant variance.