Drug Transport Flashcards
Are SLC’s associated with influx or efflux (note exception)?
Influx - Organic Anion Transporters, Organic Anion Transporting Polypeptides, Organic Cation Transporters
Effllux - Multidrug and Toxin Extrusion Transporters (MATE)
How do OAT’s work without ATP?
Linked to an a-ketoglutarate antiport
Specifically:
- OA in, aKG out
- aKG in, Na in
- K in, Na out (pumpKin!)
OAT drugs
Methotrexate
NSAIDs
Cidefovir
What inhibits OATs?
Probenecid
OAT drug interactions:
NSAIDS v. Methotrexate
They both use the same receptor.
NSAIDs can block methotrexate clearance uptake into kidney tubules–> toxicity
Relevant for cancer and rheumatoid arthritis
OAT drug interactions:
NSAIDS v. Cidefovir
They both use the same receptor.
NSAIDs can block cidefovir clearance –> nephrtoxicity
How do OATP’s work without ATP?
Linked to an a-ketoglutarate antiport
Specifically:
- OA in, bicarbonate out
Where are most OATs located?
Liver and kidney
OAT drug interactions:
Probenecid v. Cidefovir
Probenecid inhibits OAT1
Cidefovir shows severe renal toxicity
Probenecid keeps cidefovir from secretion into the proximal convoluted tubule. It is then eliminated via the glomerulus
Cidefovir is always co-administered with probenecid
Where are most OATP’s located?
liver + kidney (reabsorption), intestine (absorption)
What types of molecules do OATPs act on?
Amphipathic anions
OATP drug
Statins
OATP Inhibitors
Cyclosporin
Macrolides
OATP Interactions:
Cyclosporin v. statins
Cyclosporin inhibits OATPs, and statins are OATP substrates.
Result: Statins can’t enter the liver and be metabolized –> toxicity
OATP 1B1 v. OATP 1B115 polymorphism
Statin stays in blood –> toxicity
OCT/MATE drugs
Metformin
Cisplatin
Cimetidine
Procainamide
Main role of OCT (influx) /MATE (efflux transporter)
Renal tubular secretion of substrates
Effect of cimetidine on OCT/MATE drugs and what this means for cisplatin extretion
Cimetidine blocks OCT-mediated
renal uptake of many drugs thereby
blocking their elimination plasma concentration
In the case of cisplatin, this stops cisplatin from being taken up into the kidney, preventing nephrotoxicity
P-gp drugs
Digoxin
Loperamide
Etoposide
P-gp inhibitors
Cyclosporin
Verapamil
(Cimetidine)
How are pgp inhibitors used to target the brain?
P-gp inhibitors enhance CNS accessibility
by overcoming BBB
How do cancer cells exploit pgp properties
They use pgp/mdr transporters to excrete cancer drugs
How do rifampin and SJW affect systemic drug availability (via pgp’s)
Rifampin/St. John’s wort induce P-gp expression, increasing drug efflux and decreasing systemic
availability
