Pharmacokinetics ADME absorption, distribution

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

The pKa is an important physicochemical parameter. The analyte pKa values are especially important in regard to pharmacokinetics (ADME—absorption, distribution, metabolism, excretion) of xenobiotics since the pKa affects the apparent drug lipophilicity [59]. Potentiometric titrations and spectrophome-tric analysis can be used for pKa determination however, if the compound is not pure, is poorly soluble in water, and/or does not have a significant UV chromophore and is in limited quantity, its determination may prove to be challenging. 

Figure 1.8 Schematic representation of the pharmacokinetic processes, absorption, distribution, metabolism and excretion (ADME)...

ADME—absorption, distribution, metabolism, and elimination. These are the defining pharmacokinetic characteristics of how a drug is handled by the body. 

Pharmacokinetic studies are often referred to using the acronym ADME - absorption, distribution, metabolism and excretion -reflecting the four main areas for study. The use of such an acronym is simplistic in nature when one considers that each of the four areas is interdependent on one or more of the others, but nevertheless it is a convenient way of dividing up the studies that fall under the broad heading of pharmacokinetics. 

Abbreviations-. ADA = anti-drug antibodies ADME = absorption, distribution, metabolism, excretion CNS = central nervous system CV = cardiovascular EU = European Union IV = intravenous mAbs = monoclonal antibodies PD = pharmacodynamics PK = pharmacokinetics SC = subcutaneous U.S. = United States. 

As described previously, virtual screening and in silico design will accelerate the discovery of active lead compounds with new chemical scaffolds. The in silico prediction of physicochemical and ADME (absorption distribution metabolism elimination) properties, however, also are very critical for lead development. Actually, pharmacokinetics and toxicity have been identified as important causes of costly late-stage failures in drug development. The recently developed in silico approaches will increase model productivity in fine-tuned lead optimization to improve compound design and lead optimization. 

Pharmacokinetics is the scientific discipline that deals with the mathematical description of biological processes affecting drugs and affected by drugs. In addition to signifying the relationship of ADME (absorption, distribution. 

Various in vitro assays are widely available for profiling distribution, metabolism, and pharmacokinetics (DMPK, also referred to as ADME absorption, distribution, metabolism, and excretion). Such properties of molecules are measured to ultimately predict their in vivo behavior. The metabolic stability of molecules is assessed routinely in drug discovery units by way of medium- to high-through-put assays using hepatic microsomes or hepatocytes obtained from different species (usually rat and/or human). Permeability assays (e.g., utilizing Caco-2 or MDCK cells) together with an assessment of efflux potential are also useful to troubleshoot unexpectedly low cell activity or can help select candidates for subsequent in vivo studies. 

Part V targets applications that are organized according to specific compound classes of analytes. The role of mass spectrometry in peptide and protein characterization and in proteomics is the subject of Chapter 18. Next, the topic of carbohydrate analysis by ESI and MALDI is tackled in Chapter 19. This is followed by an examination of ESI and MALDI applications to lipid analysis (Chapter 20). Finally, the important subject of drug discovery is addressed in Chapter 21, including in vitro ADME (absorption, distribution, metabolism and excretion) profiling and pharmacokinetic screening. 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

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. 

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

It is important to understand the need for the multiple assays that are now routinely performed by most pharmaceutical companies to measure various absorption distribution metabolism and excretion (ADME) parameters to determine the pharmacokinetic (PK) properties of new chemical entities (NCEs). The goal of new drug discovery is to find NCEs that have the appropriate... 

---