Absorption, distribution, metabolism and excretion studies

Foreign clinical results are acceptable except in areas where there are immunological and ethnic differences between Japanese and foreigners. The ethnic factors are divided into two components intrinsic factors such as racial factors and physiological differences and extrinsic factors, which include cultural and environmental issues. In these cases, the MHLW may require that some bridging comparative clinical trials be performed with dose ranging protocols. This will enable absorption, distribution, metabolism, and excretion studies to be carried out on Japanese individuals and provide better dosage and indication for the Japanese people. The MHLW also requires that application be accompanied by one year of real-time stability data and that sterility test results be included. 

More recently, partially as a result of increased research sophistication and observations made in ADME (Absorption, Distribution, Metabolism, and Excretion) studies, increased attention is being given to evaluating metabolites of APIs. An old example (not being pursued because of the lack of patent protection) is the metabolite... 

ADME Studies Absorption, distribution, metabolism, and excretion studies were conducted for 24,21,17, and 19 out of the 34 biopharmaceuticals, respectively. No radiolabeled proteins were used for 20, 2,1, and 13 out of the 34... 

Absorption, Distribution, Metabolism, and Excretion. Studies of the pharmacokinetics of... 

Hop, C.E., Use of nano-electrospray for metabolite identification and quantitative absorption, distribution, metabolism and excretion studies, Cum Drug Metab., 7(5), 557, 2006. 

Absorption, Distribution, Metabolism, and Excretion. Studies monitoring the pharmacokinetics of the coal tar creosote mixture are limited. Much of the information regarding the disposition of creosote is based on indirect evidence or the pharmacokinetic information available on a single class of creosote components, the PAHs. For more information on the toxicokinetics of PAHs, please refer to the ATSDR... 

Absorption, Distribution, Metabolism, and Excretion. Studies in laboratory animals indicate that di- -butyl phthalate given orally is readily absorbed, mainly as the metabolite mono- -butyl phthalate, and subsequently, is rapidly excreted. Limited data exist regarding inhalation and dermal absorption. Studies on the absorption and metabolism of di- -butyl phthalate by the inhalation and dermal routes are needed to evaluate human health risk by these routes of exposure. 

Biotech and pharma companies outsource a number of different functions. In the discovery phase, the syntheses of building blocks, intermediates, and especially libraries are frequently outsourced, often to India or Eastern Europe. Offshoring of chemistry is frequent, that of biology less so. But ADME Absorption, Distribution, Metabolism, and Excretion) studies and animal models for preclinical development are now sometimes done in China, for example, at Shanghai s WuXi Pharmatech, whose customers currently include nearly all of big pharma and big biotech. ... 

The purpose of conducting absorption, distribution, metabolism, and excretion studies is to address the biological activity or availability of the ingredient when given to the infant. The toxicokinetics of the ingredient should be studied via the following ... 

Unlike the organ system analyses described below, absorption, distribution, metabolism, and excretion studies are relatively uniform for any new ingredient and should follow the basic guidelines of the Redbook (OFAS, 2001, 2003). Table 5-3 provides examples of... 

The overall objective of clinical trials is to establish a drug therapy that is safe and effective in humans, to the extent that the risk-benefit relationship is acceptable. The ICH process has developed an internationally accepted definition of a clinical trial as Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy. ... 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

Pharmacokinetics—The science of quantitatively predicting the fate (disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides the means of studying the absorption, distribution, metabolism and excretion of chemicals by the body. 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

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. 

Mass transfer phenomena exist everywhere in nature and are important in the pharmaceutical sciences. We may think of drug synthesis preformulation studies dosage form design and manufacture and drug absorption, distribution, metabolism, and excretion. Mass transfer plays a significant role in each. Mass transfer is referred to as the movement of molecules caused not only by diffusion but also by convection [1],... 

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. 

Absorption, Distribution, Metabolism, and Excretion. Metabolism and excretion in animals exposed to acrylonitrile by the inhalation and oral routes have been studied extensively. However, only limited data on absorption and distribution are available. Some data on humans exposed by inhalation are available. No data are available on the toxicokinetics of acrylonitrile when the exposure route is dermal. More extensive information on absorption and distribution of acrylonitrile would be valuable to fully understand the toxicokinetics of acrylonitrile. Some data on the toxicokinetics of acrylonitrile... 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of acrylonitrile in rats has been studied. Limited work in other species suggests that important species differences do exist. Further evaluation of these differences, and comparison of metabolic patterns in humans with those of animals would assist in determining the most appropriate animal species for evaluating the hazard and risk of human exposure to acrylonitrile. 

Absorption, Distribution, Metabolism, and Excretion. There are no mechanistic or quantitative studies of hexachloroethane absorption from the lungs or across the gastrointestinal tract or skin. However, absorption does occur following oral exposure based on the appearances of hexachloroethane and its metabolites in blood, urine, and exhaled air (Fowler 1969b Gorzinski et al. 1985 Jondorf et al. 1957 Mitoma... 

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