Anticipating metabolites and residues for agrochemicals is difficult, especially early in the discovery process where costs per compound must be kept low. In vitro and in silico models can both help address the challenges involved in cost-effective ways, but it is important to distinguish the job of predicting terminal metabolites and residues from the much easier task of simply predicting whether or not an active ingredient gets metabolized. Confusion can arise in part because the “metabolism” in ADMET has to be placed within the context of the other processes in the acronym – i.e., absorption, distribution, excretion and toxicity. Hepatic metabolism of a compound that is broken down at the intestinal wall or in plasma, for example, may be a demonstrable experimentally without being physiologically irrelevant. Similarly, transient intermediates that are not observable in vivo because they are subject to further metabolism or spontaneously break down may be correctly predicted by an in silico model without being a matter of regulatory concern. This talk will discuss such contingencies and how to keep them in mind when applying in vitro experimental results or interpreting software analyses, thereby minimizing the number of red herrings and false warning flags encountered early in agrochemical discovery.

Why is predicting metabolites harder than predicting metabolism?

ACS Fall 2021

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