Multiple Peaking Phenomena in Pharmacokinetic Disposition

Multiple peaking in the blood fluid concentration-time curve is a phenomenon occasionally encountered in pharmacokinetics. When it occurs, it can create difficulties in the determination and interpretation of pharmacokinetic parameters. Multiple peaking can occur as a consequence of a number of different mechanisms. These include, in addition to others, factors related to the formulation, be it the drug chemical entity itself or other formulation-related factors such as the excipients incorporated into the product design. Another contributing factor that can work in concert with the formulation is the physiological makeup of the gastrointestinal tract itself. This includes the pH and components of bile such as bile salts and phospholipids, the secretion of which is regulated by hormonal and dietary factors. In some cases, biochemical differences in the regional areas of the gastrointestinal tract, such as regiospecificity in bile concentrations and/or transport proteins, could contribute to windows for absorption that result in multiple peaking of xenobiotics. One of the most common sources of multiple peaking is contributed by biliary secretion followed by intestinal reabsorption of a drug, a process for which the term 'enterohepatic recycling' has been coined. This cause of multiple peaking is associated with special consideration in the calculation and interpretation of the drug clearance and volume of distribution. In this review, each of these various causes of multiple peaking is discussed, with incorporation of relevant examples for illustrative purposes.