Absorption, distribution, metabolism profiling

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

More recently the concept of ADMET profile (Absorption Distribution Metabolism Excretion Toxicity profile) has further streamlined the molecular pharmacology aspects of these drugs with the ultimate objective of providing efficient target directed drugs with least toxicity. 

The physical properties and pharmacokinetic profile, with data on absorption, distribution, metabolism and excretion (ADME) in animals, form an essential part of the drug selection process since the desired pharmacokinetic profile... 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

In this workflow, chemists want to draw or import a set of molecules, profile their molecular properties, such as computed ADME T (absorption, distribution, metabolism, excretion, and toxicity) properties, estimated activities against specific protein targets based on existing SAR models, and make selections based on the analysis of structural features and computed molecular properties of those singleton molecules. 

The above definition of toxicity is concerned with living animals, i.e. in vivo studies. Toxicity can also be measured in vitro using mammalian cell or bacterial cultures or subcellular fractions (e.g. for mechanistic studies). However, such toxicity estimates made in vitro may not always reflect accurately the toxicity of a chemical to mammals since absorption, distribution, metabolism and excretion in vivo can markedly alter the profile of toxicity (82UP10502) (see also Section 1.05.2.6). 

V. In vivo pharmacology pharmacokinetics pharmacology screening Animal Determine pharmacokinetic profile of ohgos, i.e., absorption, distribution, metabolism, and elimination Determine pharmacological effects of ohgos on host tissues other than desired effects... 

One major difficulty in making these predictions is the complexity inherent in pharmacokinetic or toxicokinetic data. Consider, for example, the oral ingestion of a xenobiotic. The kinetic parameters of importance here are the same whether this is a therapeutic drug taken intentionally, or if the compound was a toxicant accidentally ingested. Overall, we wish to be able to predict the concentration-time profile of the compound in the organs of the body. This involves a multitude of interacting systems responsible for absorption, distribution, metabolism, and elimination. 

Profiling of Drug Absorption, Distribution, Metabolism and Elimination in Man ... 

All of the above information will prove invaluable in determining the potential methods for rational drug delivery. Particular attention should be paid to the relative hygroscopicity of the API, of course, any stability information, as well as the impurity profile and ADMET (absorption, distribution, metabolism, excretion, and toxicity) information. In short, the more information that is available when development activities are initiated, the easier it is to avoid common pitfalls and make development decisions more rationally. 

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