Drug Metabolism discovery: candidate

Six scientific disciplines are involved in the developability characterization of a lead discovery candidate. As shown in Figure 4, these disciplines are in vivo pharmacology, bioanalytical method development, nonclinical formulation assessment, animal pharmacokinetics, drug metabolism, and toxicology. The following sections discuss each of these scientific disciplines in more detail. 

Many lead discovery candidates are transferred to the preclinical development process with insufficient characterization to assess their development potential. This lack of knowledge usually results in poorly designed experiments that are not data productive and that, in many cases, have to be repeated when a candidate shows unexpected toxicity, low and variable delivery, instability in formulation, or unacceptable pharmacokinetic and drug metabolism profiles. In all too many cases, the recognition of these problem areas results in termination of... 

In silico approaches to predict drug metabolism are of particular interest to the pharmaceutical industry as having the potential to impact the early drug discovery process as well as in the candidate selection phase. The identification of metabolic soft spots in a new chemical entity could help improve the hepatic... 

The sensitivity and selectivity brought to drug discovery by the routine use of HPLC/MS/MS has revolutionized biopharmaceutical capabilities. This impact has been realized in the form of increased throughput and decreased cycle time. In a highly significant sense, these new analytical methods have enabled the introduction of absorption distribution metabolism excretion studies much earlier in discovery than previously possible. At one time the investment of lengthy assay development for transport studies on a discovery candidate was nearly unthinkable. With HPLC/MS/MS, this barrier has been removed. Prime ADME information can be provided at the earliest stages of discovery to aid in the selection of lead candidates. 

These considerations make it important to understand the preabsorptive and first-pass metabolism characteristics of candidate drug molecules and to optimize these characteristics preclinically when possible. Drug metabolism plays a central role in modem drug discovery and candidate optimization, recent reviews have detailed how metabolism has impacted the discovery process and challenges that the field faces in the future.4-8... 

This section introduces the fundamentals of drug discovery and development, summarizing the roles of certain scientists who work within fipcos. It surveys preclinical discovery and chemical development, where many chemists find work. It also introduces other development efforts that occur when a clinical candidate has been chosen or when the choice nears. These efforts include drug metabolism, radiochemistry, and radioimmimology, and they also employ organic and medicinal chemists. 

Radiochemists and drug metabolism experts work at the interface between discovery and development research. The former scientists are basically organic chemists who synthesize labeled samples of the clinical candidate(s) for the latter. For biological researchers, they also prepare radiolabeled sam-... 

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