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).
The gastrointestinal (GI) tract varies greatly in morphological characteristics from relatively no folding in the esophagus to high degrees of folding (villi) in the small intestine (Tortora and Grabowski, 1993). The small intestinal villous epithelium is the primary mediator and barrier to GI absorption of orally administered drugs and nutrients into systemic circulation. The primary cells mediating drug absorption across the intestinal villous epithelium are the polarized columnar ente-rocytes, which are distinguished by the presence of apical membrane microvilli. The villous structure and the enterocyte microvilli provide a significant increase in the intestinal absorptive surface area (Tortora and Grabowski, 1993); however, it is the compound's physicochemical properties that dictate the route and extent of absorption.
Paracellular and transcellular diffusion are the two routes of GI permeation (Adson et al., 1995; Knipp et al., 1997; Sorensen et al., 1997). Paracellular absorption occurs via diffusion of dissolved solute between cells through the tight junctional complex and tortuous pathway in the intercellular spacing (Adson et al., 1995; Knipp et al., 1997). The paracellular pathway is quite restrictive depending on the pore size and charge of the tight junctions as well as the cell barrier's porosity. There are several physicochemical characteristics of a drug that favor paracellular diffusion including charge, hydrophilicity, shape/conformation, size, and molecular weight (Adson et al., 1995; Knipp et al., 1997).
The transcellular route is comprised of several potential parallel pathways for drug permeation including passive transcellular diffusion, ion channels, facilitated diffusion, active transport, and endocytosis (Oh and Amidon, 1999). A more comprehensive discussion on the characteristics of each transcellular route of permeation is provided by Oh and Amidon (1999).
Passive transcellular diffusion has traditionally been viewed as the most desirable route for GI drug absorption. The degree of passive transcellular permeation of a compound is also largely dependant on those physicochemical properties mentioned above, including the degree of ionization, lipophilicity, molecular weight, and shape/conformation. In the past, the pH-partition hypothesis, first postulated in the mid- to early 1900s, was used as a model for predicting the absorption and/or disposition of a drug across biological membranes based on the lipid to aqueous partition coefficients as a function of molecular ionization. Jacobs (1940) initially linked biological permeability and accumulation to pH, demonstrating a correlation between absorption and an electrolyte's degree of dissociation. In fact, much of the early work was based on the observation that the rate of drug absorption is related to the drug's degree of dissociation in solution, where drugs that exhibit a higher lipophilic versus ionic character will diffuse much more readily across biological membranes (Hogben et al., 1959). Given this clear correlation, researchers postulated that the physical barriers to drug absorption must be lipoidic in nature. The pH-partition hypothesis was then mathematically described under sink conditions based on the fraction of unionized drug in solution using Fick's first law of diffusion, assuming that aqueous boundary layer does not affect the transport process:
Fick's first law of diffusion
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