Drug candidates oral absorption potential

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. 

Amino add transporters seem to hold a great potential for intestinal absorption of drugs and drug candidates. However, overall, the information on the impact of these transporters in terms of mediating oral bioavailability of amino acid mimetics is rather limited, and systematic investigations using both in vitro and in vivo data are highly antidpated. 

At this point, the lead is chemically modified to improve potency, selectivity, bioavailability, and its pharmacokinetic profile. This means a drug candidate should be potent enough to bind properly to the target. It needs to bind specifically to the target or else it will generate potential side effects. It needs to have proper absorption (preferably orally) and distribution throughout the body, and it should be metabolized without generating any toxic substances. Lastly, it should be easily eliminated from the body. 

Final formulations, like those used for marketed drugs, are generally not used for Phase 1 studies. Formulation development represents expenditure of significant resources, the approaches used may depend on the results of future bioavailability studies, and the success of the drug candidate is still an open question. Therefore, simple formulations are most often used. For orally administered drugs, solutions are ideal as they provide flexibility in dosing and minimize potential absorption or bioavailability problems. Capsules filled with neat drug or suspensions can be employed when solutions are not feasible. 

Anesthetized rats are used for testing the side effect potential of a candidate compound on intermediary metabolism in liver, muscle and adipose tissue with subsequent effects on metabolic blood parameters (e.g. glucose, lactate, free fatty acids, triglycerides) and insulin. The use of anesthetized rats represents more a principal assessment of the pharmacological side effect potential since the candidate compound must be administered intravenously or intraperitoneally (enteral/intestinal administration should be avoided due to the anesthesia-induced decrease in intestinal motility with subsequent impairment of enteral absorption), compared to the study in conscious rats in which the candidate compound can be studied after oral administration, which in most cases represents the clinical route of administration for small molecular drugs. 

The new process, which has now become dominant, derives from the realization that a new commercially successful drug has to be conceived from the outset as meeting a significant medical need. Once a broad target area has been defined (e.g., arthritis, hypertension, schizophrenia), a search is made for actual or potential specific biochemical processes that, if modulated, would be predicted to have a beneficial fundamental effect on the course of the disease. Once the biochemical process has been defined, an in vitro assay is developed, so that the effect of any given compound on that process can be determined. With as much logic as can be mustered, candidate compounds are designed, then synthesized, and evaluated. Once the desired biochemical activity has been obtained, the active substances are evaluated in an in vivo model to establish that oral administration of the test substance results in the desired effect in an intact animal species. Should this not be the case, poor absorption and/or rapid formation of inactive metabolites may be to blame, and appropriate modification of the lead compounds will be undertaken. 

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