Drug metabolism

Our current ideas of drug metabolism have been shaped to a large extent by the landmark review by Richard Techwyn Williams in 1947 (see Detoxification Reactions, by RT Williams 1947). Prior to this, detoxification reactions were seen to be applicable mainly to poisons, and molecules which were structurally related to endogenous chemicals. Prof Williams himself wrote that "detoxification reactions exist for natural and structurally related foreign compounds; metabolism unlikely for totally foreign structures".

By 1959 however, the ideas had expanded to include drug metabolism.

Prof Williams went on to propose a schematic for drug metabolism that still applies today. Drug molecules were metabolized via a Phase I set of reactions which included oxidations, reductions and hydrolyses; and then a phase II synthetic reactions. These reactions were not necessarily detoxification reactions but could actually result in the formation of a toxic metabolite.

These series of reactions did however, convert molecules which were lipophilic to metabolites that were hydrophilic and more water soluble. It was also thought at that time, and for a long time after that, that these lipophilic drug molecules were freely permeable across membranes.

These ideas are however, currently being challenged as we increasingly recognize that drug molecules are not free permeable across membranes and do require the involvement of drug transporters. But this is a story for a later telling.