Pharmacology of Drug Transporters Flashcards
Normal endogenous function of transporter proteins
Influx: nutrients (AAs, sugars), essential metabolites (vitamins), signaling molecules (steroids, hormones)
Efflux: dietary and environmental toxins
OAT: Organic Anion Transporters Solute Carrier (SLC )
Influx transporters: organic anions against a negative membrane potential by linking to efflux of alpha-ketogluarate
alpha-ketoglutarate concentration is maintained by Na/alphaKG cotransporter (into the cell)
Sodium is maintained by Na/K pump (Na out, K in)
In LIVER AND KIDNEY (proximal tubulues)
Endogenous: cGMP, bile salts, CAC intermediates, hormones
Drugs: methotrexate (anti-cancer), NSAIDs, Cidefovir (anti-viral)
Clinical significance of OAT
Methotrexate and NSAIDS: metho for cancer/rheumatoid, NSAIDs inhibit OAT1
Metho cannot be excreted into kidney tubule/urine and plasma concentration increases to toxic levels
Probenecid and Cidefovir: cidefovir is anti-viral, causes renal toxicity (because too much can be transported into tubule). Use Probenecid to block OAT1 and prevent nephrotoxicity
OATP: Organic Anion Transporting Polypeptides Solute Carrier (SLC )
Influx transporters: electroneutral, transports using HCO3- out of cell
Expressed in gut, liver, kidney
Endogenous: bile acids, steroids, thyroid hormones
Drugs: statins, cyclosporin
Clinical significance of OATP
STATINs take up into liver by OATP1B1
If there is a SNP of OATP (ie 1B1*5), decreased STATIN uptake into liver, increased plasma concentration of STATIN and toxicity
Cyclosporin also inhibits OATP1B1 and can have the same effects (STATIN toxicity)
OCT: Organic Cation Transporters Solute Carrier (SLC )
Influx transporters: mediate simple passive diffusion of substrates (small, + charged compounds)
Expressed in gut, kidney, liver, and other tissues
Endogenous: monoamine NT, creatine, catecholamines
Drugs: Cisplatin (chemo), metformin (diabetes), cimetidine (H2 receptor antagonist), procainamide (antiarrhythmic)
MATE: Multidrug and Toxin Extrusion transporters
Efflux: organic cations
Secondary active transport-> drive by H+ antiport
Play a major role in excretion of +charged drugs
Overlapping substrate specificity with OCTs
Responsible for secretion of OCT-transported substrates in luminal brush border surfaces
Renal tubular secretion of cationic drugs into urine, hepatic elimination of cationic drugs into bile
Clinical significance of OCT/MATE transporters
SNPS affect OCT/MATE activity; metformin (anti-diabetic) can increase in plasma concentration and be toxic
Drug interactions: cimetidine (treats acid peptic disorder) prevents renal elimination of OCT-dependent drugs, ie can increase plasma concentration of procainamide (anti-arrhythmic)
Cisplatin (chemo) is use-limited b/c of nephrotoxicity. Cimetidine can block cisplatin uptake into kidney and PREVENT cisplatin-induced nephrotoxicity
P-glycoprotein/ Multidrug resistant protein (MDR1)
ABC
Gut, kidney, liver
Pumps drug across membrane (for elimination)
Broad substrate specificity, typically bulky/hydrophobic structure with neutral/+ charge
Drugs: digoxin, loperamine, cyclosporin (inhibitor), rifampin and st. John’s work (inducers)
Clinical significance of P-glycoprotein/MDR1 transporter
Cyclosporin inhibits efflux activity
In gut, kidney, liver this leads to decrease drug elimination of drugs such as digoxin (narrow therapeutic window)
Rifampicin and St. John’s wort are induces of P-gp and other ABC, which increases drug efflux and reduces drug efficacy
Loperamines is used in treatment of diarrhea, potent substrate of P-gp and does not cross BBB, but cyclosporin inhibits P-gp and will allow loperamide to cross BBB and cause respiratory depression
Breast Cancer Resistant Protein BCRP
ABC
Expression: gut enterocytes and liver; BBB; mammary epithelium
Substrates: neutral, - charged compounds
Endogenous: riboflavin (vit B12)
Drugs: STATINs, antibiotics, anti-cancer drugs
Multidrug resistant proteins (MRP)
ABC
Expression: broadly expressed in many tissues
Substrates: amphipathic molecules with at least one - charge
Endogenous substrates: glutathione, glucuronide, sulfate-conjugates
Drugs: methotrexate, antivirals
BBB
Tight junctions between endothelial cells
ABC family efflux pumps
Excludes most drugs other than those small (
