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