Absorption, distribution, metabolism review

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

During the past decade, numerous articles reviewing the effects of aging on pharmacokinetic processes (i.e., absorption, distribution, metabolism, and elimination) have been published [115 124h]. An outline of the observations made in these reports is supplied in Table 5. The absorption process is the only process that will be covered in depth in this chapter, as this is the process that can most easily be manipulated through formulation techniques. 

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. 

Two recent reviews 22 contain considerable information on the absorption, distribution, metabolism, and excretion of phencyclidine. 

The absorption, distribution, metabolism and excretion of coumarin in humans have been reviewed (Cohen, 1979 Fentem Fry, 1993 Pelkonen et al., 1997 Lake, 1999). 

The frequently used acronym LADME, which stands for liberation, absorption, distribution, metabolism, and excretion, broadly describes the various biopharmaceutical processes influencing the pharmacokinetics of a drug. Since each of aspect of LADME can influence the pharmacokinetics of a drug and ultimately the design of controlled release delivery devices, this section will review and explain the relationship between LADME processes and eight common pharmacokinetic parameters (F, K, Vd, tm, Cl, ha, tmax, Cp jnax). 

Metabolism. Absorption, distribution, metabolism, and excretion of thioglycolic acid have been reviewed (20). In summary, 353-thioglycolic acid was absorbed significandy after application to the skin of rabbits. After intravenous injection, the greatest counts of radioactivity were found in the kidneys, lungs, and spleen of monkey and in the small intestine and kidneys of rat. Most of the radioactivity was rapidly excreted in the urine in the form of inorganic sulfate and neutral sulfur. 

The section on general toxicological and biological parameters reviews and summarizes chemical data and basic toxicity information available on the agent of interest and reviews data on absorption, distribution, metabolism, and excretion in humans and experimental animals. 

The pharmacokinetic process of absorption, distribution, metabolism, and excretion within the lungs is an enormous subject area and readers are referred to specific reviews for further details [38-43], Of particular interest may be the subject of absorption enhancer methodologies for lung delivery, which is beyond the scope of this chapter [44],... 

Many thousands of descriptor types have been developed over the years of chemical research. This short review is not intended to summarize these efforts in detail. Todeschini and Consonni have already provided a reference book for this purpose. Commercial and academic software for generating molecular descriptors has proliferated over the recent years. Todeschini s book lists software packages known in the year 2000. Speed of calculation, descriptor quality and diversity should be considered in selecting software. For example, absorption, distribution, metabolism, excretion, toxicity (ADMET) Predictor (Simulations Plus, Inc.) works at a rate of 250,000 molecules per horn calculating 272 molecular and 44 atomic descriptors in the following categories ... 

The toxicity to the nervous system depends on the delivered dose and exposiue duration. In the case of pregnant women, pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern PAH disposition within the mother and the nervous system of children. Moreover, unique physiological features, such as the presence of a placental barrier and the gradual development of the blood-brain barrier influence PAH disposition and thus modulate developmental neurotoxicity. Because CNS effects are dependent upon windows of susceptibility when the lowest dose and shortest duration of exposure to environmental PAHs will have the greatest negative impact on brain development, a susceptibility exposure paradigm has proven to be the most reliable model in which to study developmental insult. The intent of this chapter was to review... 

Other HTS assay advances include the us-e of microorganisms such as bacteria and yeast, the cloning and expression of mammalian receptors in microorganisms, probing protein-protein inlcraclions. and veiy importantly. DNA and protein arrays. These are loo involved to discuss here, but excellent reviews exi.sl.- - The increasing use of HTS to screen fora molecule s absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties has been covered as well. ... 

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