Biomedical Engineering Reference
In-Depth Information
Paracellular Transport
•
Hydrophilicity
•
Molecular size and shape
•
pK
a
of the ionizable groups
Active Transcellular Transport
• Affinity (K
m
), capacity (V
max
/J
max
)
• Expression level (constitutive,
induced)
• Function (drug-drug and drug-nutrient
interactions, competitive inhibition)
...
P
barrier
=
P
para
+
P
passive, trans
+
P
active
1
, trans
+
+
P
active
n
, trans
Transcellular Transport
•
Lipophilicity
-Hydrogen-bonding potential
-Hydrophobicity
•
Molecular size and shape
•
pK
a
of the ionizable groups
FIGURE 6.2.
Some of the rate-limiting mass transfer resistances/characteristics of the parallel
paths that oligopeptide-based compounds typically encounter as they traverse cell barriers.The
effective permeability of the physiological barrier is a function of all competing transport
pathways.
on potential paracellular and transcellular events. Adson et al.
4
demonstrated that the
delineation of the paracellular and transcellular mass transfer resistances from ob-
served cell-based assay permeability studies was possible. Several studies conducted
by Burton and colleagues further demonstrated that hydrogen-bonding potential may
provide a better means for predicting the potential passive transcellular diffusion of
peptides.
163
-
166
Based on these observations, several studies conducted with larger
oligopeptides demonstrated that conformation and lipophilicity may dictate the extent
of passive paracellular and transcellular peptide transport across Caco-2 and bovine
brain microvessel endothelial cell (BBMEC) barriers.
167
,
168
These studies focused
on passive diffusion; however, permeation of smaller di- and tripeptides and peptide-
based analogs of similar size may also have affinity for oligopeptides transporters
that can be rate controlling for their absorption. A summary of the characteristics for
each parallel pathway of transport based on an extension of these and other findings
is presented in Figure 6.2.
Although it is clearly evident that oligopeptide transporters play a major physi-
ological role in the absorption of various nutrients and peptidelike xenobiotics, the
pharmaceutical industry has yet to fully realize and exploit the potential advantages
associated with targeted delivery to these transporters. Probably the most readily ap-
parent application of oligopeptide transporter research is the marketability of Valtrex
(valacyclovir) comparative to Zovirax (acyclovir). Comparing clinical trial data (be-
low), the addition of a valyl moiety to the ether end of acyclovir increased the bioavail-
ability from approximately 15% with Zovirax
169
to 54% with Valtrex.
170
Although
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