Pharmacokinetics ADME

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. 

Ricerca offers in vivo and in vitro ADMET services. Specifically, it provides in vitro assays for CYP inhibition, metabolism, ADME, pharmacokinetic, and metabolism profiling (330). 

Drug discovery demands for the optimization of chemistry space with the in-house decisions around target potency,invivopharmacology,ADME/pharmacokinetics optimization, and dose range finding to guide the suc-... 

The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Pharmacokinetics refers to activities within the body after a dmg is administered. These activities include absoqrtion, distribution, metabolism, and excretion (ADME). Another pharmacokinetic component is the half-life of the drug. Half-life is a measure of the rate at which drains are removed from the body. 

Poor pharmacokinetics and toxicity are important causes of costly late-stage failures in drug development. It is generally recognized that, in addition to optimized potency and specificity, chemical libraries should also possess favorable ADME/Tox and druglike properties [77-80]. Assessment of druglike character is an attempt to decipher molecular features that are likely to lead to a successful in vivo and, ultimately, clinical candidate [81-83]. Many of these properties can be predicted before molecules are synthesized, purchased, or even tested in order to improve overall lead and library quality. 

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. 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Boobis, A., Gundert-Remy, U., Kremers, P., Macheras, P., and Pelkonen, O., In silico prediction of ADME and pharmacokinetics Report of an expert meeting organised by COST B15, Eur. J. Pharm. Sci., 2002, 37, 183-193 in press. 

Pharmacokinetic/ ADME (absorption, distribution, metabolism, elimination) studies including bioanalytical method development... 

Pharmacokinetics relates to the fate of a drug in the body, particularly its ADME, i.e. its absorption into the body, its distribution within the body, its metabolism by the body, and its excretion from the body. 

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

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... 

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

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]. 

Pharmacokinetics and ADME Correlation with Pharmacodynamics Low dose High dose General Toxicity... 

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