Chemical Biology: Approaches to Drug Discovery and Development to Targeting Disease

Chapter 5: Pharmacokinetics of Drug Candidates

Ronald E. White

Schering-Plough Research Institute, Kenilworth, New Jersey

Pharmacokinetics is a mathematically based discipline that describes the time course of uptake, distribution, and elimination of a drug in an organism. This chapter explains the physiologic basis and clinical interpretation of the various pharmacokinetic parameters, such as half-life, clearance, and oral bioavailability. Because of the central importance of pharmacokinetics to the clinical use of drugs, the determination of pharmacokinetics is required at several points in the research and development cycle of new drug candidates. The rationale and methods of determination are discussed.

The therapeutic effectiveness of drugs generally can be related to the concentrations achieved at the physiologic site of action and to the length of time that effective concentrations are maintained [1]. For instance, molecules of an antibiotic must reach the site of infection (e.g., inner ear, lung, or bladder) to interact with the molecular target (typically an enzyme) in the infecting bacteria. Similarly, cough suppression or relief of clinical depression may require a medicine to penetrate the blood–brain barrier to access molecular targets (typically pharmacologic receptors) in the central nervous system. Therefore, an assessment of the effectiveness of the therapy partly depends on our ability to monitor concentrations of the drug in these organs. However, because often ...