Mass Transport via Cellular Barriers and Endocytosis - Intracellular Delivery: Fundamentals and Applications - page 8

P eff can be estimated experimentally by measuring the drug loss across the lumen at
any given segment:

 

Q C

out lumen ,

P =

lumen

ln

  eff

2 p rl C

 

in lumen ,

Where C out,lumen and C in,lumen are the concentrations of drug leaving and entering
the lumen respectively, r is the radius, l the length of the lumen segment and
Q lumen is the experimentally determined luminal flow rate. P eff is dependent on the
physico-chemical properties of the drug which ultimately determine drug parti-
tioning between the hydrophilic exterior of the membrane ( P aq ) and the lipophilic
bilayer ( P m ):

111

=+

PPP

eff aq m

2.1.2 Facilitated Passive Diffusion and Active Transport

Some of the endogenous substances or nutrients (e.g. vitamins, ions, sugars, amino
acids) are absorbed through the processes such as facilitated passive diffusion and
active transport. Both involve the drug reversibly binding to a carrier protein at the cell
membrane exterior, followed by the carrier-substrate complex being transported across
the lipid layers by proteins embedded in the membrane (Tsuji and Tamai 1996 ).
Carrier-mediated diffusion is characterized by selectivity, saturability and regional
variability (Tanaka et al. 1998 ). The carrier transports only substrates with a relatively
specific molecular configuration and the process is limited by the availability of carri-
ers. Saturation of carriers results in a non-linear dose-response relationship. Facilitated
passive diffusion does not require energy expenditure by the cell and therefore
transport against a concentration gradient does not occur through this mechanism.
Transport against a concentration barrier can be achieved by active transport,
which requires both associated carrier proteins and energy expenditure by the cell.
Membrane transporters can be divided in two major super-families: ATP-binding
cassette and solute carriers (SLC). These carrier proteins are expressed in different
degrees in different regions and of particular importance are those present in the
intestinal epithelia, hepatocytes, and proximal tubules of the kidney and in the
endothelium of the blood-brain barrier, as shown in Fig. 2 . Among the specialized
small-intestine transport systems are organic anion transporting polypeptides
(OATP), Oligopeptide Transporter 1 (PEPT-1 and SLC15A1), and mono-carboxylic
acid transporters (MCT1 and SLC16A1) (Giacomini et al. 2010 ). In contrast to
these specialized drug transport mechanisms, there are processes that obstruct drug
penetration by expelling therapeutics from cells. These include membrane efflux
pumps. An example is cell surface p-glycoprotein. P-glycoprotein actively opposes
drug absorption by transporting many drugs from the intracellular environment to
the intestinal lumen (Hunter and Hirst 1997 ).