proximal tubule cells by transporters at the basolateral membrane. Once inside the cells, these drugs are then transported out of the cells into the tubule lumen by transporters at the apical membrane and subsequently eliminated in the urine. The alliance between transporters at both the basolateral membrane and the apical membrane of the kidney proximal tubule cells ensures the clearance of the drugs from the body.
1.6 CLASSIFICATIONS OF DRUG TRANSPORTERS
Drug transporters can be classified in a number of different manners, including as efflux transporters versus influx transporters, secretory transporters versus absorptive transporters, and ABC transporters versus SLC transporters.
1.6.1 Definition of Efflux and Influx Transporters
Drug transporters can be categorized as efflux or influx transporters according to the direction they transport substrate across the cell membranes. This classification 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.
1.6.2 Definition of Absorptive and Secretory Transporters
The other way of classifying drug transporters is from a pharmacodynamic or pharmacokinetic 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 blood‐brain‐barrier and placenta are discussed, the definition needs to be modified. The brain and fetus have been traditionally 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 absorptive transporters.
1.6.3 Relationship Between Influx/Efflux and Absorptive/Secretory Transporters
An absorptive transporter does not necessarily mean that it influxes a substrate. Similarly, a secretory transporter does not have to be an efflux pump. For example, 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 membrane 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. Intestinally expressed organic anion‐transporting polypeptide 1A2 (OATP1A2) is localized on the apical domain of enterocytes. It can take up (i.e., influx) orally administered drugs into the enterocytes for their subsequent exit across the basolateral membrane into the blood stream, so OATP1A2 is considered an absorptive transporter. Therefore, influx transporters can function as either absorptive or secretory transporters depending on the tissue and on the membrane domain where they are expressed.
1.6.4 ABC Transporters and SLC Transporters
Most of the drug transporters can also be molecularly and mechanistically classified as a member of the ABC transporter family or the SLC transporter family (Table 1.1).
ABC (ATP‐binding cassette) transporters is a family of membrane transport proteins that require ATP hydrolysis for the transport of substrates across membranes. Therefore, ABC transporters are primary active transporters. The protein family derives its name from the ATP‐binding domain found on the protein. The best studied drug transporters, which are classified as ABC transporters, are multidrug resistance protein (MDR), multidrug resistance‐associated protein (MRP), and breast cancer resistance protein (BCRP).
Some of the SLC (Solute Carrier) transporters utilize an electrochemical potential difference of the transported substrate and are therefore classified as facilitated transporters; other SLC transporters utilize an ion gradient, such as sodium and proton gradients across the membrane produced by the primary active transporters, and transport substrates against an electrochemical difference. These transporters are classified as secondary active transporters. In contrast to ABC transporters, SLC transporters do not possess ATP‐binding sites. Most drug transporters belong to SLC transporters.
TABLE 1.1 Classifications of representative drug transporters
| Transporters family | Family member | Gene name | Human chromosome locus | References |
|---|---|---|---|---|
| Organic cation transporter (OCT) | hOCT1 | SLC22A1 | 6q26 | [1] |
| hOCT2 | SLC22A2 | 6q26 | [1] | |
| hOCT3 | SLC22A3 | 6q26‐q27 | [2] | |
| Zwitterion transporters | OCTN1 | SLC22A4 | 5q31.1 | [3] |
| OCTN2 | SLC22A5 | 5q31 | [4] | |
| OCTN3 | SLC22A21 | 5q31 | [5] | |
| FLIPT1 | SLC22A15 | 1p13.1 | [6] | |
| CT2 (OCT6) | SLC22A16 | 6q21‐q22.1 | [7] | |
| Organic anion transporter (OAT) | OAT1 | SLC22A6 | 11q13.1‐q13.2 | [8] |
| OAT2 | SLC22A7 | 6p21.2‐p21.1 | [9] | |
| OAT3 | SLC22A8 | 11q11.7 | [10] | |
| OAT4 | SLC22A11 | 11q13.1 |
|