Absorption, distribution, metabolism elimination/excretion, and toxicity

This chapter describes some of the approaches and techniques used currently to derive in silico models for the prediction of absorption, distribution, metabolism, elimination/excretion, and toxicity (ADMET) properties. The chapter also discusses some of the fundamental requirements for deriving statistically sound and predictive ADMET relationships as well as some of the pitfalls and problems encountered during these investigations. It is the intention of the authors to make the reader aware of some of the challenges involved in deriving useful in silico ADMET models for drug development. 

The increase in new structures generated each year has not resulted in the expected increase of marketed new drugs annually. This has amongst others been attributed to poor pharmacokinetic (PK) properties of the CDs, and as much as 40% of the attrition rate of CDs has been related to poor PK profiles [1]. Given this, reliable screening filters for factors such as absorption, distribution, metabolism, elimination/excretion, and toxicity (ADMET) are highly desirable [2-4], Indeed, the considerable effort that has been invested in the development of experimental absorption filters, for example, cell monolayers for permeability determinations [5, 6] and the turbidimetric method for solubility measurements [7],... 

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]. 

Pharmacokinetic interactions may occur during one or more of the pharmacokinetic processes whereby the drug reaches its site of action and is then eliminated (i.e. absorption, distribution, metabolism and excretion). Such interactions may result in a change in the drug concentration at the site of action with subsequent toxicity or decreased efficacy. 

Pharmacokinetics is the study of how the body affects an administered drug. It measures the kinetic relationships between the absorption, distribution, metabolism, and excretion of a drug. To be a safe and effective drug product, the drug must reach the desired si te of therapentic activity and exist there for the desired time period in the concentration needed to achieve the desired effect. Too little of the drug at such sites yields no positive effect (MTC) leads to toxicity. For intravenous administration there is no absorption factor. Total body elimination includes both metabolic processing and excretion. 

An optimization step, that deals with the improvement of the lead structure. The optimization process takes primarily into account the increase in potency, selectivity and toxicity. Its characteristics are the establishment and analysis of structure-activity relationships, in an ideal context to enable the understanding of the molecular mode of action. However, an assessment of the pharmacokinetic parameters such as absorption, distribution, metabolism, excretion and oral bioavailability is almost systematically practised at an early stage of the development in order to eliminate unsatisfactory candidates. 

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