What do drug transporters and drug metabolizing enzymes (DMEs)--as well as the various regulatory proteins involved in the absorption, distribution, metabolism and excretion (ADME) of drugs--really do (1)? To those coming from a non-pharmaceutical background, this seems a very reasonable, if not urgent, question. What do they really do? What is their true biological function?

To understand this, we must go beyond the classic multi-specific “drug” transporters and “drug” metabolizing enzymes (2, 3). We must consider the oligo-specific and mono-specific transporters, enzymes and regulatory proteins (eg, nuclear receptors, kinases) they often work with--in the contexts of both pharmacokinetics and endogenous metabolism. The list of proteins is quite large; a rough estimate is 500–1000 (4). In other words, perhaps as much as 5% of the human genome is dedicated to handling endogenous small molecules that bear a molecular resemblance to numerous pharmaceuticals.