Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, Monkeys, and Humans

The process of discovering and developing effective therapeutic drugs is intricate, resource-intensive, and time-consuming. In the United States, the journey from drug development to market availability spans around 10–15 years, with an average cost exceeding $3.0 billion. Most small molecular drugs are administered orally due to their convenience and cost-effectiveness, making oral bioavailability a pivotal parameter in drug discovery. Therapeutic variability can be attributed to poor oral bioavailability, underscoring its significance. This chapter examines the critical role of oral bioavailability in drug development, especially its impact on therapeutic variability and patient safety. Evaluation of a new chemical entity's pharmacokinetic profile, including oral bioavailability, is routinely conducted in animal models such as rats, dogs, and monkeys during early drug discovery. These assessments, in conjunction with in silico and in vitro data, aid in projecting pharmacokinetic profiles in humans. Nonetheless, challenges persist in predicting oral bioavailability due to species-specific physiological and metabolic differences. This chapter critically reviews the similarities and disparities in absorption, distribution, and metabolism mechanisms affecting oral bioavailability in humans, rats, dogs, and monkeys, offering insights essential for informed drug development decisions.