Bioavailability drug discovery process

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

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. 

Identification of metabolic reactions at an early phase can significantly affect the drug discovery process, because bioavailability, activity, toxicity, distribution and final elimination all depend on metabolic biotransformations [1], Once obtained, this information can help researchers judge whether or not a potential candidate should be eliminated from the pipeline or modified to reduce the affinity for CYP antitarget enzymes. 

The ability of combinatorial chemistry to synthesize large numbers of compounds has stimulated interest in developing in silico methods that can predict bioavailability as part of the drug discovery process. Current computational methods can provide separate estimates of the solubility and intestinal permeability of candidate drug molecules even before they are synthesized (33). However this approach has not yet been perfected/ and the computational requirement of the... 

Bioavailability is a composite property that requires PK studies to assess, but just as the routine measurements of simple in vitro potency is the first step in building chnical potency, routine computational estimates or measurements in model systems can play a key role in optimizing compounds for bioavailability in man. Once again, such parameters used to be examined only late in the drug discovery process, but nowadays the essential triad potency, solubility, and cell permeability is taken into account from the very beginning of a project. Absorption and cell permeability can be modeled in a number of in silico and in vitro systems, as discussed in the following sections. The still more important property of bioavailability, where metabolism can play a major role, is discussed in more detail later in the chapter. 

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