Absorption, distribution, metabolism, and excretion properties

Tarbit, M.H. and Berman, High-throughput approaches for evaluating absorption, distribution, metabolism and excretion properties of lead compounds, Curr. Opin. Chem. Biol., 2, 411, 1998. 

Approaches for Evaluating Absorption, Distribution, Metabolism and Excretion Properties... 

Comparative Toxicokinetics. The toxicokinetics database is wholly inadequate with respect to comparing toxicokinetics across species, largely because of the dearth of baseline data regarding absorption, distribution, metabolism, and excretion in any species after exposure to mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, or polyalphaolefin hydraulic fluids. Also, no studies were located on the toxicokinetic properties of hydraulic fluids in humans. 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

It is important to understand the need for the multiple assays that are now routinely performed by most pharmaceutical companies to measure various absorption distribution metabolism and excretion (ADME) parameters to determine the pharmacokinetic (PK) properties of new chemical entities (NCEs). The goal of new drug discovery is to find NCEs that have the appropriate... 

From a DMPK perspective, a common goal is to be able to compare multiple compounds based on their absorption, distribution, metabolism and excretion (ADME) properties as well their preclinical PK properties [8, 12-22]. Therefore, lead optimization typically is performed as an iterative process that uses the DMPK data to select structural modifications that are then tested to see whether the DMPK properties of the series have been improved. This iterative process is shown schematically in Fig. 13.2. Clearly an important element for the successful lead optimization of a series of NCEs is the ability to perform the DMPK assays in a higher throughput manner. The focus of this chapter will be to discuss ways that mass spectrometry (MS), particularly HPLC-MS/MS can be used to support the early PK studies for NCEs in a higher throughput manner. 

As discussed in Section 2.3, Toxicokinetics, the specific toxicokinetic behavior of 1,4-dichlorobenzene in children (and immature laboratory animals) has not been reported. Based on its physicochemical properties, it is anticipated that the absorption, distribution, metabolism, and excretion of... 

The effect of any chemical at a biological target depends on its ability to attain a target site concentration that exceeds the threshold required to ehcit the response. The intensity and duration of the response depends on the toxicokinetic properties of the compound (absorption, distribution, metabolism, and excretion) and the nature of the target site interaction (reversible, irreversible). If recovery is complete between successive exposures, no cumulative toxicity is to be expected. However, a short-term acute exposure could potentially add to the long-term burden of a persistent chemical and be relevant for the magnitude of the chronic effect. 

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... 

Pharmacokinetics (i.e. study of the movements of a medication) antipsychotics and other medications show differences in absorption, distribution, metabolism and excretion as a result of their different chemical structures and pharmaceutical preparations (capsule, tablet, injectable) and in relation to the conditions within the body (see Chapter 5). The transfer of a medication from the blood into the brain tissue across the so-called blood brain barrier, its binding to specific brain structures and thus its actions depend on the physicochemical properties of the molecule. The interplay of these and other factors explains why antipsychotics of different chemical structures are not equally effective milligram for milligram (Table 1.2 column 3) and why they differ with regard to onset and duration of action. 

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