ADME studies pharmacokinetics

A series of pharmacokinetic and ADME studies was performed with imi-glucerase in order to assess clearance and targeting of imiglucerase in vivo. Because there was no suitable animal model for Gaucher disease, these studies were performed in normal animals. 

The nonclinical species used in the ADME studies are based on toxicology species used in the long-term safety evaluation of the compound. These are typically rodent (rat and mouse) and nonrodent (rabbit, dog or monkey) species. The study is designed to closely mimic the toxicology studies keeping the dose selected, the route of administration, and the dosing vehicle as close as possible to those used in the actual studies. The amount of radioactive dose administered in animal species is usually determined by the pharmacokinetic... 

The objectives of rat tissue distribution studies are to (1) obtain radioactivity distribution in rat tissues after single doses of C or H labeled compounds, (2) obtain the pharmacokinetic parameter of radioactivity ( C or H) in rat major tissues or organs, and (3) calculate dosimetry for human ADME study. Animals used for this study are pigmented male Long-Evan rats, 250 g body weight, 6-7 weeks. The numbers of rats used for a tissue distribution studies... 

Pharmacokinetic, toxicokinetic, and absorption, distribution, metabolism, and excretion (ADME) studies... 

Pharmacokinetic, toxicokinetic, and ADME studies. As a part of the toxicity studies, or in other studies, toxicokinetics should be performed. Toxicokinetics is defined as the generation of pharmacokinetic data in order to assess systemic exposure. These data can be used in the interpretation of toxicology findings and their relevance to clinical safety. For meaningful results to be generated, analytical methods must have been developed with the analytes (API, metabolites, etc.) and matrices (plasma, whole blood, tissue. 

The measurement of the concentration of drug-derived materials in biofluids, especially blood (plasma) and urine, is essential for the pharmacokinetic study of the rates of absorption, distribution, metabolism, and excretion. These are known as ADME studies. All such analyses are based on the addition of a known amount of an internal standard to an aliquot of the biofluid, followed by coextraction of the standard and the analyte after a period of equilibrium. The extract is purified and normally a chromatographic separation is carried out prior to detection. 

An important feature of drug development is the estimation of pharmacokinetic parameters in animal models. Pharmacokinetics is the study of the time dependence and mechanism of absorption of a compound dosed into the body, its distribution throughout the fluids and other body tissues, the sequential metabolic transformations of the compound and its first-generation metabolites, and the elimination of the original compound and its metabolites (whence the common abbreviation ADME studies). The usual experimental raw data consist of concentrations of the test compound (and sometimes of its metabolites) in body tissues and body fluids (blood plasma, urine) as a function of time following a single dose. Extraction of quantitative parameters characterizing this behavior is determined by the theoretical model used to interpret the data. For example, if the dose is administered intravenously and the compound concentrations are measured in the blood, there will be an immediate drop of compound concentration with time as the compound is re-distributed, metabolized and excreted, but if an oral dose is used (as... 

It may be helpful to examine the main elimination pathways, whether hepatic or renal, for the product in question. Routine radiolabelled metabolism studies are, however, not generally appropriate. One of the principal aims of the ADME and pharmacokinetic data should be to aid in the interpretation of the toxicity studies by providing comparative exposure data to the pharmacologically active moiety in animal species and 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. 

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. 

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. 

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

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]. 

For a drug to interact with a target, it has to be present in sufficient concentration in the fluid medium surrounding the cells with receptors. Pharmacokinetics (PK) is the study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs. It analyzes the way the human body deals with a drug after it has been administered, and the transportation of the drug to the specihc site for drug-receptor interaction. For example, a person has a headache and takes an aspirin to abate the pain. How does the aspirin travel from our mouth to reach the site in the brain where the headache is and act to reduce the pain ... 

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