The success of a drug’s journey through the body is measured in the dimensions of absorption, distribution, metabolism, and elimination (ADME). The ideal oral drug will be rapidly and completely absorbed from the alimentary canal and will find its way directly and specifically to its site of action. It will not bind to or interact with related receptors, and it will not bind non-specifically to passing serum proteins. The ideal compound may be a substrate for the liver enzymes and transporters that break down or clear alien compounds from the body, but in an entirely predictable fashion. Neither will it induce their activity (or indeed, inhibit them). Consequently, there is no risk that breakdown of this ideal compound will give rise to any toxic metabolites and every chance that the compound will have an appropriate half-life, passing gradually through the kidneys without harming them.
In the real world, of course, chemical compounds rarely exhibit this ideal combination of characteristics. Few are fully absorbed from the gut. The percentage that does cross is distributed at various sites in the body including, but not exclusively, the intended site of action. A large proportion passes through the liver where it may be metabolized by enzymes, such as the P450 oxygenases, sugar transferases, and drug transport system. Drugs may induce the activity of these molecular “bouncers” whose main biological role is to show the door to non-nutritious compounds, which the rather more welcoming guardians of the gut, lung, and other epithelia have foolishly allowed entry. The door in this case, of course, is usually the kidney. Elimination, the ultimate fate of all foreign compounds, including drugs, is relatively easy to measure, but much harder to explain or predict for any particular compound. It is, of course, highly dependent on the complex series of molecular, cellular, and physiological process that constitute drug absorption, distribution, and metabolism.
The ADME properties of a drug, together with its pharmacological properties (as, say, a highly selective agonist or antagonist of a discrete biological target like a receptor), are conventionally viewed as part of drug development—the process of making a molecule as effective as possible as a medicine. Toxicology—the T in ADMET—is the art of making sure that the molecule causes no harm, regardless of what good is does. While a drug that kills is hardly likely to be a good drug, innovation in toxicology tends to be constrained by the need to fulfill regulatory requirements. Toxicology tends to be a “box-ticking” exercise in which the extensive panel of molecular, cellular, and whole animal tests is statutory and immutable. Not that the regulatory authorities do not want to see data on ADME as well; they are especially interested in whether drugs induce liver enzyme activity because this may have a bearing on drug–drug interactions.
John Hodgson, Nature Biotechnology, 2001, 19, 722-726.
