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A General Overview
• The primary function of transporters is to transport endogenous substances,
such as hormones, glucose, and amino acids; however, many of these
transporters also transport xenobiotics. It is these drug transporters that are
of importance when considering drug disposition and drug response.
• Drug transporters are localized to barrier membranes of the body
responsible for xenobiotic entry and exit. They are expressed in organs of
absorption, such as the intestine, and clearance organs including the liver
and kidney.
• Transporters are also expressed on membranes that separate particularly
susceptible organs from the rest of the body, including the blood–brain and
blood–placenta barriers, where they facilitate the influx of nutrients and
efflux of potentially harmful xenobiotics.
• Because of their location on barrier membranes, transporters have an
important role in drug pharmacokinetics and pharmacodynamics.
Transporters can have a role in drug absorption and can facilitate or prevent
drug entry into the body.
A General Overview
• The role of transporters in drug distribution can also affect drug
response by allowing or preventing drug access to the site of action.
• One of the most interesting roles of drug transporters is their indirect
effects on drug metabolism. Transporters can restrict or allow a drug’s
distribution into organs that contain drug-metabolizing enzymes,
particularly the liver and the intestine. In this regard, there can be
extensive transport-metabolism interplay, and transport or
metabolism can be the rate-limiting process controlling drug
elimination.
• Transporters are also responsible for transport and removal of drug
metabolites.
• Transporters have a significant role in drug excretion, as they are
present in the kidney and on the canalicular membrane of the liver
where they can facilitate drug elimination into the urine or bile,
respectively.
MECHANISMS OF MEMBRANE TRANSPORT
Transport mechanisms most commonly used by therapeutic agents include
passive diffusion and facilitated transport.
MECHANISMS OF MEMBRANE TRANSPORT
• Passive diffusion is the simplest way for a drug to pass through a
membrane and depends only on the existence of a concentration
gradient for a molecule across the membrane. Because of the
lipophilicity of biologic membranes, diffusion is energetically
unfavorable for drugs that are relatively hydrophilic, particularly for
drugs that are predominantly ionized at physiologic pH, and these
molecules require facilitated transport. Facilitated transport refers to
any transport aided by a facilitating protein.
• Similar to diffusion, passive facilitated transport depends only on the
existence of a concentration gradient and involves movement of
molecules down this gradient.
• Active transport uses a separate energy source to move molecules
against their concentration gradient. Drug transporters can use either
passive or active transport mechanisms. Paracellular transport
(transfer of substances between cells of an epithelial cell layer) and
transcytosis (vesicular transfer of substances across the interior of a
cell) are less commonly used mechanisms of membrane transport.
• Molecules can use one or more of these mechanisms to cross
biological membranes.
CLASSIFICATION OF TRANSPORTERS
Facilitative Versus Active Transporters
CLASSIFICATION OF TRANSPORTERS
Primary Versus Secondary Active Transporters
• Primary active transporters most commonly use
adenosine triphosphate (ATP) as an energy source
for substrate transport.
• Secondary active transporters use the concentration
gradient of another substance, such as protons or
sodium ions, but also other ionic endogenous
substances as energy sources to drive transport.
CLASSIFICATION OF TRANSPORTERS
Primary Versus Secondary Active Transporters
Types of drug transporters. Primary active transporters use ATP and have the ability to
transport substrates against their concentration gradient. Secondary active transporters
used gradients created by primary active transport to transport drug substrates. Facilitated
transporters only transport substrates down their concentration gradient. Transporters that
transport drug substrates are shown in red, whereas those shown in gray provide driving
forces for drug transport. The same direction, referred to as symport, or in opposite
directions, referred to as antiport.
CLASSIFICATION OF TRANSPORTERS
Influx Versus Efflux Transporters
• Influx transporters transport substrates from extracellular spaces into
cells. Efflux transporters transport substrates out of cells. Transporters are
usually responsible for either drug influx or drug efflux, but in some cases
facilitate both types of transport.
CLASSIFICATION OF TRANSPORTERS
Secretory Versus Absorptive Transporters
Secretory transporters facilitate drug clearance and are responsible for transport of drugs
from the blood, such as excretion into the urine. Absorptive transporters allow a drug
access into the blood, such as those facilitating absorption in the gut or reabsorption in
the kidney. A transporter can be both secretory and absorptive depending on its
physiologic locations.