ADME stands for absorption, distribution, metabolism, and excretion. It is an abbreviation immediately recognized in pharmacology as these four stages constitute the basic kinetics of a drug candidate in a living organism. When liberation, or toxicity, or both get connected with ADME studies, we get the variations LADME, ADMET, or LADMET.
ADME studies determine the viability of a drug candidate, without compromising its potency. Eino Nelson first presented these four terms together in a 1961 article in the Journal of Pharmaceutical Sciences. ADME replaced the earlier words resorption, distribution, consumption, and elimination that Torsten Teorell had used in 1937.
In its original use, ADME was simply a signifier that quantified the drug candidate getting into the body (A), proceeding inside the body (D), transforming inside the body (M), and exiting the body (E). However, in recent times, some diversifications have happened.
Absorption now refers to crossing the gastrointestinal wall. Distribution refers specifically to the movement of the drug between compartments, i.e. the stipulated amount of body fluids. The terms metabolism and excretion or elimination, however, have retained their original meanings.
Why ADME Studies are Important
There are two primary aims of ADME assays during the preclinical stage of drug development. One is to eliminate drug candidates with weak pharmacokinetic profiles. That restricts resource wastage to a considerable extent. The other goal is to ascertain compliance with statutory requirements.
ADME Assays for Elimination
ADME studies of chemical compounds with small molecules are crucial during the initial stage of drug development. ADME deficiency can lead to the elimination of otherwise potent drug candidates. There are instances of stronger drug candidates becoming considerably less active in vivo due to poor ADME adequacy.
Kenakin (2017) mentions in chapter 7 of Pharmacology in Drug Discovery and Development (Academic Press, 2nd edition) that in 1991, the failure rate due to ADME imbalance stood at 40%. Application of cost-effective ADME assays reduced failure rates to 10% in 2000 and to less than 1% by 2008.
Measurements of the bioavailability of the drug candidate in blood, plasma, or other predetermined body fluids during a specific time period yield ADME pharmacokinetic properties. Such data determine future in vitro and in vivo studies with reference to dosage and rate of application.
A number of assays related to ADME pharmacokinetics are conducted during the preclinical stage. The three most commonly used assays for assessing absorption rate are PAMPA (parallel artificial membrane permeability assay), Caco-2 and MDCK (Madin-Darby canine kidney) permeability. PAMPA is the most economical of these assays.
However, there have been studies to reflect that PAMPA and Cco-2 assays synergize well to offer more accurate results. Sometimes Caco-2 and MDCK permeability assays also get combined to increase accuracy.
CYP inhibition assays also constitute a typical element in ADME studies. These tests were conducted at a later stage earlier. In contemporary practice, they have been moved up in the drug development ladder to determine drug-drug interactions.
ADME Studies for Compliance
Safety Testing for Drug Metabolites: Guidance for Industry issued by the Federal Drug Administration (FDA), US, has resulted in drug metabolite identification and profiling also becoming an important part of early ADME assays. The FDA first issued the guidance in 2008 and has recently revised it in 2016.