Rational Drug Design
Ligand Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET)

Introduction:

In order for a ligand to become a useful drug, it needs to be acceptable in terms of absorption, distribution, metabolism, excretion and toxicity (ADMET). Effective in silico techniques for extimating such properties can expedite design of a useful drug.

Absorption

Before a drug can do anything useful it needs to be introduced into an appropriate body system with a route to the target. The drug might be ingested, in which case it will need to pass through some portion of the membranes of the digestive system. The drug might be injected into the bloodstream, in which case it will need to pass through capillary pores, or be injected to be passed through capillary pores in the other direction. Injected drugs may be placed intramusclarly, subcutaneously or dermally form control over the rate of transport into the bloodstream (fastest to slowest). Even in the case of direct infusion into the organs containing the target, the target is likely to still be within one or more containing membrane. In almost all cases the drug needs to pass through a membrane of some kind, i.e. to be absorbed, to have a chance of achieving bioavailability.

Distribution

Except in the case of direct infusion, the drug will need to be transported through the body to the site or sites containing the target. The blood stream supplemented by the lymphatic system is the primary initial distribution system for drugs. Note that many of the capilary pores in the brain are blocked by the blood-brain barrier. Some drugs have major systemic pickup into tissues generally from the bloodstream, but many drugs are primarily taken up in the liver for initial metabolic changes and further distribution.

Metabolism

The liver has primary responsibility for metabolism (chemical breakdown) of ligands by redox enzymes. The resulting metabolites may be more or less active than the original drug. In some cases this first pass through the liver will completely deactivate the drug

Excretion

Buildup of drugs and their metabolites in the body can cause serious, and sometimes fatal side-effects. There are three major bodily systems available for removal of drugs an their metabilites: 1) the liver to the bile system to the gut; 2) the kidneys to the bladder; and 3) the lungs. Care must be taken in the design of a drug to ensure the excretion does not damage these organs.

Toxicity

A drug may cause damage to organ or pathway, resulting in mortality (death) or morbidity (disease). The may be the result of an overdose of the drug, or binding to an unintended target, or genetic damage, etc.

See https://en.wikipedia.org/wiki/Toxicity and https://en.wikipedia.org/wiki/Toxicity.