Pharmacokinetics ADME characteristics

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. 

The traditional role of preclinical drug metabolism in pharmaceutical research has been to define absorption, distribution, metabolism, and excretion (ADME) of potential drug compounds for regulatory fiUngs. This role has expanded over the past 5 years to include support of early drug discovery. Consequently, the number of compounds whose ADME characteristics need to be defined has expanded the work now encompasses thousands of compounds annually rather than the traditional tens of compounds. At the same time, the focus has evolved from merely defining a compound s own fate in the body to include the identification of potential liabiUties, such as parameters that Unfit in vivo pharmacokinetics (PK). 

Although traditional octanol/water distribution coefficients are still widely used in quantitative structure-activity relationships (QSAR) and in ADME/ pharmacokinetic (PK) studies, alternatives have been proposed. To cover the variability in biophysical characteristics of different membrane types, a set of four solvents has been suggested - sometimes called the critical quartet [49-51], The 1,2-dichloroethane (DCE)/water system has been promoted as a good alternative to alkane/water due to its far better dissolution properties [50, 51], but it may be used only rarely due to its carcinogenic properties. 

Benzodiazepinones such as 4 [14] have been claimed as PDE2 inhibitors, as have oxindoles related to 5 [15]. Compound 5 was reported to have an IC50 of 40 nM against PDE2. Preliminary ADME screening showed 5 to have the physicochemical and pharmacokinetic characteristics that should allow use as a tool to study PDE2 function in more detail [16]. 

The efficacious plasma or tissue concentration largely defines the course of ADM E optimization. Pharmacokinetic features have a significant impact on safety. Off-target effects often limit the use of efficacious doses, as they make safety margins too narrow. Thus, the combination of PK characteristics and off-target activities are largely responsible for an acceptable TI. 

During preclinical development, the structure, physical and chemical characteristics, and stereochemical identity of the IND/CTA candidate are fully characterized. This information, for example, is required for the chemical manufacture and control (CMC) section of the IND. Appropriate bioanalytical methods are developed for the evaluation of pharmacokinetics, typically a series of studies focusing on absorption, distribution, metabolism, and excretion (ADME) in toxicology species, as well as systemic exposure and metabolism in toxicological and clinical studies. 

ADME—absorption, distribution, metabolism, and elimination. These are the defining pharmacokinetic characteristics of how a drug is handled by the body. 

Cook, C.E. Pyrolytic characteristics, pharmacokinetics, and bioavailability of smoked heroin, cocaine, phencyclidine, and methamphetamine. In Miller, M.A., and Kozel, N.J., eds. Methamphetamine Abuse Epidemiologic Issues and Implications. National Institute on Drug Abuse Research Monograph 115. DHHS Pub. No. (ADM) 91-1896. Washington, DC Supt. of Docs., U.S. Govt. Print. Off,... 

From this discussion, the efficacy of a drug is not determined by its pharmacodynamic characteristics alone, but efficacy also depends, to a large extent, on the pharmacokinetic parameters of the drug, because ADME processes control the rate and extent to which an administered dose of a drug reaches its site of action. 

Kaminskas, L.M., Boyd, B.J., Porter, C.J., 2011a. Dendrimer pharmacokinetics the effect of size, structure and surface characteristics on ADME properties. Nanomedicine (London)... 

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