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TopTranslating The Acronym Adme
Despite its extensive use, the ADME acronym refers to a rather broad set of not well defined physiological properties, forming a network, which if translated to particular measurements, results in interlinked outcomes. The most common assays which shape the ADME profiling may be interpreted in this context (Wishart, 2007). Thus, in vitro permeability assays, such as Caco2, MDCK, PAMPA, are related to the ‘A’ and ‘D’ of the acronym, while % human intestinal absorption (% HIA), next to ‘A’ and ‘D’, involves also ‘M’, if metabolism in the gut wall is considered. Blood-brain barrier penetration is related to ‘A’, ‘D’ and ‘M’. Volume of distribution and plasma protein binding are related to ‘D’, while the latter is also related to ‘E’ considering that high PPB results in greater half-life. Oral bioavailability is related to ‘A’ and ‘E’ and elimination or plasma half-life to ‘M’ and ‘E’. Cytochrome P450 (CYP) metabolic stability as a measure of the resistance or tendency of a drug to first-pass effect is related to ‘M’ and ‘E’ (Wishart, 2007).
Having answered to a great extent the problem of oral bioavailability and permeability, as deduced by the latest statistics, the network of all other assays can be considered to be related to efficacy, reinforcing the sustained role of ADME properties in the multi-objective environment of drug discovery process. More to the point, safety, often incorporated as T in ADME(T) is shaped by several endpoints including metabolite-mediated toxicity, inhibition of certain CYP isoforms, being directly related with ‘M’, off target activities and promiscuity as well as tissue and organ accumulation (drug induced hepato-toxicity and cardiotoxicity) and effect on membrane phospholipids (drug induced phospholipidosis).