OVERVIEW OF DRUG TRANSPORTER FAMILIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 4

1.5.1. Definition of Efflux and Influx Transporters
Drug transporters can be categorized as efflux or influx transporters according to the
direction in which they transport substrate across the cell membranes. This classifi-
cation is often observed in the literature where drug transport studies are performed
at the cellular level. With this definition, transporters that pump the substrates out of
the cells are called efflux transporters , whereas transporters that transfer substrates
into cells are called influx transporters .
1.5.2. Definition of Absorptive and Secretory Transporters
The other way of classifying drug transporters is from a pharmacodynamic or phar-
macokinetic point of view. In such a classification, the transporter that transfers its
substrates into the systemic blood circulation is called an absorptive transporter ,
whereas the transporter that excretes its substrates from the blood circulation into
bile, urine, or the gut lumen is known as a secretory transporter . However, when
absorptive or secretory transporters in the brain blood-brain barrier and placenta are
discussed, the definition needs to be modified. The brain and fetus have traditionally
been considered as two “isolated” compartments in the human body. In drug therapy,
many strategies have been utilized to achieve either enhanced or reduced penetration
of drugs into these two compartments. Conventionally, the transporters facilitating
drug penetration into the brain or fetus are referred to as absorptive transporters.
1.5.3. Relationship Between Influx-Efflux and Absorptive-Secretory
Transporters
An absorptive transporter does not necessarily mean that it influxes a substrate. Sim-
ilarly, a secretory transporter does not have to be an efflux pump. For example, the
organic anion transporter OAT1, present at the basolateral membrane of the kidney
proximal tubule, is an influx transporter based on its role of taking up drugs from the
blood into the proximal tubule cells for their subsequent exit across the apical mem-
brane into the urine for elimination. However, considering its overall role of removing
drugs out of the blood circulation into the urine, OAT1 is a secretory transporter. In-
testinally expressed organic anion-transporting polypeptide-A (OATP-A) is localized
on the apical domain of enterocytes. It can take up (i.e., influx) into the enterocytes
orally administered drugs for their subsequent exit across the basolateral membrane
into the bloodstream, so OATP-A is considered an absorptive transporter. Therefore,
influx transporters can function as either absorptive or secretory transporters, depend-
ing on the tissue and on the membrane domain where they are expressed.
1.5.4. ABC and SLC Transporters
Most drug transporters can also be molecularly and mechanistically classified as a
member of the ABC or the SLC transporter family (Table 1.1). ABC (ATP-binding
cassette) transporters are a family of membrane transport proteins that require ATP