Introduction: Guanidino-containing compounds are well-known for their important biological roles in vivo. In a rational drug design process, the guanidino group is frequently adopted to mimic the arginine residue of the endogenous substrate and secure the affinity of the drug to the target. However, due to their inherent polarity and positive charge in the gastrointestinal tract, it is difficult for guanidino-containing compounds to be orally absorbed by passive diffusion. Hence, guanidino-containing compounds are frequently associated with low oral bioavailability.
Areas covered: In this review, we present the barriers and challenges toward the oral absorption of guanidino-containing compounds, provide an overview of the research that has been done so far in the area, and summarize recent advances and future directions in the mechanistic enhancement of the intestinal absorption of drugs containing the polar guanidino functionality. For instance, application of several different prodrug approaches, a novel recently developed ion-pairing strategy and the utilization of advanced formulations are discussed.
Expert opinion: While additional research is required to allow efficient and facile solutions to low oral bioavailability of guanidino-containing compounds, novel and exciting strategies have been developed in recent years. Although challenging, the development of a potent guanidino-containing compound into an orally administered drug is becoming an achievable target.