P-glycoprotein
P-glycoprotein (P-gp, MDR1) is a primary active efflux transporter with a molecular weight of 170 kDa, belonging to the ABC superfamily and consisting of 1280 amino acids. P-gp is the product of the -gene (formerly: ). P is for , ABC is for .
Occurrence
P-glycoprotein is found on various tissues of the human body. It is localized at the apical membrane of cells:
- Small and large intestine (enterocytes): transport back into the intestinal lumen.
- Liver (canalicular membrane): transport into the gall bladder.
- Blood–brain barrier, placenta, blood-testis barrier: barrier function.
- Kidney (proximal tubule): elimination into the urine.
Function
Substrates enter the protein from the inner portion of the lipid bilayer via openings. P-gp transports its substrates unidirectionally and against the concentration gradient out of the cell membrane with ATP consumption. P-gp provides a transport barrier for many substances, especially xenobiotics (substances foreign to the body) and pharmaceutical agents. It plays a role in detoxification, protecting the body and sensitive organs from unwanted substances by preventing them from being absorbed or actively excreted in bile or urine.
In cancer therapy
P-glycoprotein was originally discovered in multidrug-resistant CHO cells in 1976 (Juliano, Ling, 1976). P-gp is a factor involved in the development of so-called (MDR), which is the development of cross-resistance of tumors to mechanistically and structurally different cytostatic drugs. As a result, anticancer drugs do not reach their site of action inside the cell and remain ineffective.
P-gp substrates
P-glycoprotein has exceptionally broad substrate specificity. It transports hundreds of predominantly hydrophobic substances with molecular weights ranging from 330 to 4000 Da. These include, for example (selection):
| Antidiarrhoica: | Loperamide |
| Antihelminthics: | Ivermectin |
| Antihistamines: | Bilastin |
| Antithrombotics: | Dabigatran |
| Beta blockers: | Talinolol, celiprolol |
| Calcium channel blockers: | Diltiazem, verapamil |
| Glucocorticoids: | Dexamethasone |
| Cardiac glycosides: | Digoxin |
| HIV protease inhibitors: | Indinavir, ritonavir, saquinavir. |
| Immunosuppressants: | Ciclosporin, Tacrolimus. |
| Neuroleptics: | Acepromazine |
| Prokinetics: | Domperidone |
| Setrone: | Ondansetron |
| Statins: | Atorvastatin |
| Cytostatic drugs: | Colchicine, doxorubicin, etoposide, methotrexate, paclitaxel (Taxol), vinblastine, vincristine |
Digoxin is a well-studied example and is relevant because of its narrow therapeutic range. Many substrates of P-gp are also simultaneously metabolized by the CYP3A4 enzyme. Thus, the drugs are additionally subject to a metabolic barrier.
Drug Interactions
There is much evidence that P-gp exerts an important influence on the pharmacokinetics of its substrates. Therefore, drug-drug interactions are possible, particularly through inhibition or induction of P-gp. P-gp inhibitors: Agents that inhibit P-glycoprotein can increase absorption, bioavailability, and distribution-for example, to the central nervous system. At the same time, elimination is reduced. Furthermore, inhibitors can reverse the resistance of cancer cells to cytostatic drugs. Examples: Quinidine, verapamil, clarithromycin, erythromycin, itraconazole, mefloquine P-gp inducers: conversely, when P-gp inducers are administered concomitantly, the barrier function of P-gp is increased and elimination is promoted.Examples: Rifampicin, St. John’s wort.