ADME oral study

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. 

IPEC-US (intended clinical route)a Acute oral and dermal toxicity, skin and eye irritation, and skin sensitization. Bacterial gene mutation and chromosome damage. ADME (intended route). 28-day toxicity (2 species by intended clinical route) Short-term use studies. 90-day toxicity (most appropriate species). Teratology (rat and/or rabbit). Genotoxicity assays. Additional assays (conditional) 1 Short-/midterm studies. One-generation reproduction. Chronic toxicity (rodent and nonrodent) and carcinogenicity (conditional)... 

PYA copolymer Bioavailability enhancer Single-dose toxicity (in rat and dog) and maximum tolerated dose/short-term (2wks—oral) (in rat and dog) toxicity as well as 2 in vitro and 1 in vivo genotoxicity studies. ADME studies with 14C-labelled material are underway and a 3-6 mo toxicity study in the rat is planned No adverse effects seen to date 41... 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

In search for potent and systemically available inhibitors of the matrix metalloproteinase MMP-8 (Matter et al. 1999 Matter et al. 2002) following oral administration, a local ADME model was derived to support lead optimization. For an internal series of inhibitors on the tetrahydroisoquinoline scaffold, hydroxamic acids for zinc ion binding in 3-position are essential for MMP affinity in first generation inhibitors. However, those compounds are characterized by insufficient pharmacokinetic properties and low systemic exposure following oral administration. Driven by X-ray and 3D-QSAR studies (CoMFA), alternative Zn2+ binding groups like carboxylates were... 

An oral ADME (absorption, distribution, metabolism, excretion, following oral administration of the pesticide) study may also be of utility in refining the risk assessment. If a default value for dermal absorption of 100 % is applicable based on the physico-chemical properties of a substance and an appropriate oral ADME study is available, the results of this study may be used to refine the default value for dermal absorption. It is required that the oral absorption is determined at low dose levels in experimental animals, in order to obtain an accurate estimate of the oral absorption. Based on theoretical grounds and supported by a comparison of oral and dermal absorption data available for twelve pesticides, it is assumed that dermal absorption will not exceed oral absorption (Hakkert et al unpublished data). 

FDA s biopharmaceutics classification system, BCS [5], serves as a guide for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms. BCS relies on two ADME properties, passive permeability and solu-... 

The disposition of xenobiotics can be considered to occur in four interrelated phases (i.e., absorption, distribution, metabolism, and excretion, collectively abbreviated as ADME). The major routes for the absorption of xenobiotics include skin, lungs (or gills), and the parenteral routes—intravenous (i.v.), intraperitoneal (i.p.), subcutaneous (s.c.), and intramuscular (i.m.). The commonest route for administration in toxicology studies is per oral (p.o.) administration, with absorption of the test compound via the gastrointestinal (GI) tract the per-oral route is also the commonest route for exposure to a wide variety of environmental xenobiotics by fluid or food intake. 

Metabolic profiles of urine and fecal samples generated in ADME studies provide information about the extent of metabolism and routes of excretion for parent and metabolites. The excretion of radioactivity after administration of gemopatrilat to healthy human volunteers shows that the compound is excreted in both urine and feces with most of the radioactive dose excreted by 48 h postdose. Based on urinary excretion, at least 55% of the dose is absorbed when administered orally. Figure 9.4 shows the comparative urinary and fecal profiles of orally administered gemopatrilat in rat, dog, and human (Wait et ah, 2006). These types of data representations help understand the quantitative and qualitative differences in metabolism across species. As can be clearly seen in Fig. 9.4, the drug is extensively metabolized in all species. 

FIGURE 10.9 Representative plasma metabolite profiles of a radiolabeled drug candidate in rats (a), dogs (b), and humans (c). The pooled plasma samples from radiolabeled ADME studies after an oral administration were collected around the maximum concentration of the drug. The radioactivity profiles were determined by offline HPLC-TopCount (four functions per min and 10 min counting time). Approximately, 400 9000 DPM of radioactivity was injected. 

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... 

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