IntestinalTransporters in Drug Absorption

Abstract

Effective drug therapy relies on the interplay between the pharmacokinetics and pharmacodynamics (PK/PD) of the agent upon administration. During the initial stages of drug discovery, numerous studies are performed to assess the pharmacological effectiveness of new chemical entities (NCEs) to select a lead compound(s) that offers the greatest promise for therapeutic efficacy. While the ability of a drug to bind to a therapeutic target is critical to its clinical success, the ultimate effectiveness is also a function of its ability to reach the therapeutic target in sufficient concentrations to mitigate or treat the ailment. Therefore, the pharmacokinetics of any NCE must also be evaluated early in the drug discovery stages to enhance the rational selection of a lead compound from the many NCEs that are screened, based on not only biological activity but also potential in vivo bioavailability. Bioavailability is defined by the US FDA as “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action” (21 CFR 320.1(a)). The overall bioavailability is largely determined by the absorption, distribution, metabolism, and excretion (ADME) of selected compounds in targeted patient populations.While ADME involves transport/ permeability processes across cellular barriers in numerous tissues, we will restrict our discussion to intestinal absorption (absorptive influx) and excretion (secretory efflux).