(AKA: Biotransformation)

A large number of enzymes in the body metabolise drugs. Although some serve other functions, most of these evolved a few million years ago, presumably as a means of removing substances that were formed by the body or toxins and other substances found in the diet. [A caveman unable to remove toxins would have had little chance of reproducing for some time after a meal of elephant ovaries - especially if his partner had eaten the testicles]. In order to excrete toxins (and drugs) effectively they must be made more water-soluble and less lipid soluble. It is also useful to remove any biological activity in the process. The reason the excretion of toxins is aided by water solubility is that higher concentrations can remain in solution in the bile, gut or urine when they are excreted. They must also have low lipid solubility to reduce reabsorption across the gut wall cells after excretion into bile or across the renal tubule cells after excretion into urine.

Biotransformation is done by two major types of enzymatic changes: imaginatively named phase-I and phase-II reactions. Phase-II reactions, also known as conjugation reactions, involve attaching a relatively large water-soluble molecule (e.g. glutathione, glucuronic acid, sulphate) to the drug. The complex is then water soluble and generally inactive. However, not all drugs or toxins have a reactive oxygen group to undergo conjugation reactions.

Thus, the need for Phase-I reactions involves making the drug more reactive. However, because the drugs are only slightly altered, the resulting substance (metabolite) may have biological activity or indeed be far more toxic or active than the parent substance. The majority of phase 1 reactions occur in the liver (cytochrome P450 enzymes), but other organs such as the kidney, pancreas and lungs have enzyme capacity. Sometimes the solubility of the metabolite is such that it may be excreted without further transformation but often it then undergoes further metabolism by a Phase II reaction.

The three main Phase I reactions are:

• Oxidation: Oxidation is the addition of oxygen and/or the removal of hydrogen. Most oxidation steps occur in the endoplasmic reticulum
• Reduction: Add hydrogen or remove oxygen
• Hydrolysis: Addition of water with breakdown of molecule. In blood plasma (esterases)and liver

These Phase I and Phase II processes have varying anatomical distribution and capacity. As a consequence some generalisations can be made:

• Conjugative metabolism (Phase II) can be described as high capacity, low specificity and anatomically robust: There is a lot of it, it can attempt to alter a wide range of molecules and it is distributed so widely that localised anatomical insults are unlikely to affect its capacity
  • It is therefore hard to saturate and relatively resistant to disease

• P450 metabolism (Phase I) is low capacity, highly specific, genetically determined and located in sites that are frequently affected by disease. It is almost the opposite of conjugative metabolism. In the liver it is anatomically sited relatively far from energy sources, with high concentrations around the portal vein.
  • It is therefore the site of much of the clinically important altered drug metabolism mediated by disease or drug interactions

See also:

• 1.1.1.1 Bioavailability and Absorption
• 1.1.1.2 Distribution
• 1.1.1.4 Elimination
• 1.1.1.5 Clearance
• 1.1.1.6 Models (eg. compartmental, physiologic)