MAMMALIAN OLIGOPEPTIDE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 107

of these cells impart further barrier functionality to the small intestine, excluding many
compounds that may be harmful to the organism or detrimental to cellular function. 2
Based on these barriers, the physicochemical nature of a compound dictates the route
and extent of its intestinal absorption.
Compounds traverse biological barriers through either paracellular or transcellular
routes. 4 - 6 Paracellular absorption occurs by diffusion of dissolved solute between
cells through the tight junctional complex, or zonula occludens, and the tortuous
intercellular pathways. 4 , 5 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. In
contrast, the transcellular route comprises several potentially parallel pathways for
drug permeation, including passive transcellular diffusion, ion channels, facilitated
diffusion, active transport, and endocytosis. 7 The perceived mechanism of barrier
permeation is highly dependent on a number of physicochemical properties of the
drug, or xenobiotic, such as its net overall charge, hydrophilicity, shape/conformation,
size, and molecular weight. 4 , 5 Transcellular transport of a compound is also highly
dependent on a number of physiological factors, some of which are discussed below.
Although the passive paracellular diffusion of hydrophilic amino acids and peptides
is possible, size restrictions, secondary structural considerations, and charge-charge
interactions through this pathway largely preclude it from serving as a primary mech-
anism of permeation of many small peptides, oligopeptides, and protein-based com-
pounds. Due to these physiological restrictions, a majority of amino acids and peptides
require that absorption occur via the transcellular route. However, the physicochem-
ical properties of amino acids and peptides, including hydrophilicity and charge,
generally favor a hydrophilic permeation route (i.e., paracellular diffusion) and pre-
vent their passive transcellular diffusion through the hydrophobic cellular membrane.
Given these restrictions as well as those observations concerning the intestinal ab-
sorption of undigested dipeptides, such as carnosine and anserine, researchers have
realized that the bulk of di- and tripeptide absorption occurs through the function of
active, concentrative transporter proteins.
Numerous classes of transporter proteins have been identified to date, each with
different and sometimes overlapping substrate specificities, capacities and affinities
as well as specific tissue, cellular, and temporal expression patterns. Not surprisingly,
the physicochemical properties of a compound dictate its interactions with transporter
proteins. Considering that transport is a multifaceted process, variability due to overlap
of the substrate selectivity of transporters in passive diffusion due to the lipophilic
character and potential solubility differences may result in fluctuations in the observed
net membrane transport for a substrate. Notwithstanding other potential sources of
variability, the net observable transport of amino acids and di- and tripeptides is
mediated by a number of different transporter families. Di- and tripeptide transport
is, however, generally believed to be attributable to the activity of the proton-coupled
oligopeptide transporter [POT; SLC15 (solute carrier)] superfamily of transporters.
Several comprehensive reviews can be found describing the common charac-
teristics of the oligopeptide transporter proteins. 8 - 13 To date, four mammalian
members of the POT superfamily have been identified and described function-
ally (Table 6.1). The currently known peptide transporters include peptide trans-
porters 1 and 2, PepT1 (SLC15A1) and PepT2 (SLC15A2), and peptide/histidine