Transporters
Not all passage across membranes is through passive absorption, there are a number of proteins involved in transporting molecules/ions into and out of cells, probably >350. Transporters probably exist in every membrane. Many were discovered after upregulation in drug-resistant tumor cells, they can have a significant impact on the pharmacokinetics of endogenous and exogenous compounds For these reasons the regulatory authorities US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) request data on the effects of novel drugs on transporter protein activity. It is possible to evaluate some transporters in in vitro systems (Caco-2, LLC-PK1:MDR1) See Absorption. Transporters can have an enormous influence on the absorption, distribution or elimination of a drug. The best understood is ABCB1 also known as P-gp, MDR1 (mdr1 in rodents) this transporter is present in the blood-brain barrier, in the gut, on hepatocytes, and the kidney. It is also one of the transporters found to be up-regulated in some drug-resistant tumors.
Major Human Transporters
| Gene | Aliases | Tissue | Substrate | Inhibitor | Inducer |
| ABCB1 | P-gp, MDR1 | intestine, liver, kidney, brain, placenta, adrenal, testes | digoxin, fexofenadine, indinavir, vincristine, colchicine. topotecan, paclitaxel | ritonavir, cyclosporine, verapamil, erythromycin, ketocoanzole, itraconazole, quinidine, elacridar (GF120918) LY335979, valspodar (PSC 833) | rifampin, St John’s Wort |
| ABCB4 | MDR3 | liver | digoxin, paclitaxel, vinblastine | ||
| ABCB11 | BSEP | liver | vinblastine | ||
| ABCC1 | MRP1 | intestine, liver, kidney, brain | adefovir, indinavir | ||
| ABCC2 | MRP2, CMOAT | intestine, liver, kidney, brain | indinavir, cisplatin, | cyclosporine | |
| ABCC3 | MRP3, CMOAT2 | intestine, liver, kidney, placenta, adrenal | etoposide, methotrexate, tenoposide | ||
| ABCC4 | MRP4 | ||||
| ABCC5 | MRP5 | ||||
| ABCC6 | MRP6 | liver, kidney | cisplatin, daunorubicin | ||
| ABCG2 | BCRP | intestine, liver, breast, placenta | daunorubicin, doxorubicin, topotecan, rosuvastatin, sulfasalazine | elacridar (GF120918) | |
| SLCO1B1 | OATP1B1, OATP-C OATP2 | liver | rifampin, rosuvastatin, methotrexate, pravastatin, thyroxine | cyclosporine rifampin | |
| SLCO1B3 | OATP1B3, OATP8, | liver | digoxin, methotrexate, rifampin, | ||
| SLCO2B1 | SLC21A9, OATP-B | intestine, liver, kidney, brain | pravastatin | ||
| SLC10A1 | NTCP | liver, pancreas | rosuvastatin | ||
| SLC10A2 | ASBT | ileum, kidney, biliary tract | |||
| SLC15A1 | PEPT1 | intestine, kidney | ampicillin, amoxicillin, captopril, valacyclovir | ||
| SLC15A2 | PEPT2 | kidney | ampicillin, amoxicillin, captopril, valacyclovir | ||
| SLC22A1 | OCT-1 | liver | acyclovir, amantadine, desipramine, ganciclovir metformin | disopyramide, midazolam, phenformin, phenoxy-benzamine quinidine, quinine, ritonavir, verapamil | |
| SLC22A2 | OCT2 | kidney, brain | amantadine, cimetidine, memantine | desipramine, phenoxy-benzamine quinine | |
| SLC22A3 | OCT3 | skeletal muscle, liver, placenta, kidney, heart | cimetidine | desipramine, prazosin, phenoxy-benzamine | |
| SLC22A4 | OCTN1 | kidney, skeletal muscle, placenta, prostate, heart | quinidine, verapamil | ||
| SLC22A5 | OCTN2 | kidney, skeletal muscle, prostate, lung, pancreas, heart, small intestine, liver | quinidien, verapamil | ||
| SLC22A6 | OAT1 | kidney, brain | acyclovir, adefovir, methotrexate, zidovudine | probenecid, cefadroxil, cefamandole, cefazolin, | |
| SLC22A7 | OAT2 | liver, kidney | zidovudine | ||
| SLC22A8 | OAT3 | kidney, brain | cimetidine, methotrexate, zidovudine | probenecid, cefadroxil, cefamandole, cefazolin, |
ABC:ATP-binding cassette transporter superfamily; SLC: solute-linked carrier transporter family; SLCO: solute-linked carrier organic anion transporter family; MDR1: multi-drug resistance; MRP: multi-drug resistance related protein; BSEP:bile salt export pump; BCRP: breast cancer resistance protein; OAT: organic anion transporter; OCT: organic cation transporter; NTCP: sodium taurocholate co-transporting polypeptide; ASBT: apical sodium-dependent bile salt transporter.
In vitro models
In vitro transporter assays are usually carried out with either intact cells or isolated cell membranes over expressing the transporter of interest. The advantage of in vitro assays is that they can be performed with relatively high throughput and low costs as compared to in vivo assays. Cell lines that are mainly used for this type of assays consist of cells that polarise in vitro such as transfected MDCKII or LLC-PK cells over expressing the transporter of interest described in the Absorption section.
Metrabase
The Metabolism and Transport Database (Metrabase) is a cheminformatics and bioinformatics resource that contains curated data related to human small molecule metabolism and transport, Journal of Cheminformatics 2015, 7:31 DOI. Currently it includes interaction data on 20 transporters, 3438 molecules and 11649 interaction records manually abstracted from 1211 literature references and supplemented with data from other resources as shown in the image below taken from the original publication.
Metrabase is accessible via an online user interface at http://www-metrabase.ch.cam.ac.uk, and allows users to search the database by protein or compound. Search by protein is the main feature. It allows retrieval of all compounds interacting with the selected protein and shows their action types and links to the literature references from which the data originated. Search by compound allows name, structure, substructure and similarity searches. These are supported by the ChemDoodle 2D sketcher for structure drawing and the Mychem cartridge (for MySQL) , which performs cheminformatics-specific functions. The similarity search employs the FP2 fingerprint of Open Babel and the exact search compares InChI strings. Furthermore, users can retrieve tissue expression data and access information held in the UniProt and HGNC databases following the links provided in the list of the proteins. A database dump is also available for download enabling users to install their own local copy of the database. MySQL Workbench can be used as an interface: even though knowledge of SQL may not be required to display records of all tables and save them in other formats, such as TSV or CSV, it is needed to fully exploit the database in this manner.
Currently the database contains details for the following transporters, Name(Number of Compounds): ASBT (82), BCRP1 (980), GLUT1 (83), LAT1 (6), MCT1 (38), MDR1 (1,182), MRP1 (194), MRP2 (519), MRP3 (133), MRP4 (66), OATP1A2 (112), OATP1B1 (444), OATP1B3 (344), OATP2A1 (16), OATP2B1 (365), OATP3A1 (13), OATP4A1 (9), OCT1 (506), OSTA (0), OSTA/OSTB (6), OSTB (0), PEPT1 (475).
Worth looking at the Human Membrane Transporter Database.
Updated 6 December 2019