3.2 - OATs and OCTs Flashcards
What are the SLC transport protein superfamily
- Family of secondary active / facilitated transporters
- Translocate solute molecules across cellular membranes
- Superfamily of related proteins (66 subfamilies, 450+ members)
- SLC22 subfamily is noteable (next card)
SLC22 subfamily
- Part of SLC transport protein superfamily
- SLC22 family consists of 30 transporters split into two main subfamilies:
☞ OATs (organic anion transporters)
☞ OCTs (organic cation transporters)
The SLC22 proteins have two main roles - drug transporters where drugs ‘piggyback’ on these transporters to get to target tissue
- transport of endogenous metabolites + signalling molecules transporting these around the body
Organic Anion Transporters (OATs)
- polyspecific so not very specific
- anionic substrate transporters (negatively charged substrates) eg cyclic nucleotides, amino acids etc)
- Eleven OAT family members
- Commonly localised to epithelial cells
- (tend to exist in cells that act as a barrier between fluid compartments eg CSF + plasma, urine + plasma)
- Expressed in many tissues eg kidney, liver, brain, retina + placenta
Organic cation transporters (OCTs)
- polyspecific so not very specific
- Cationic substrate transporters (tend to bind to cations)
- Often work together with other transporters to transport drugs
- Six OCT family members
- OCT transporters facilitate diffusion ☞ driving force for solute movement is electrochemical gradient
- Expressed in many tissues (eg adipose, brain, heart, glands, immune cells etc)
Examples of drugs affected by OCT activity
*ie their concentration in target tissues is dependent on OCT activity)
- amiloride diuretic that treats hypertension
- atenolol β blocker that treats angina + hypertension
- cisplatin chemotherapy drug for a range of cancers
- lidocaine anaesthetic
- metformin antidiabetic drug for type 2 diabetes
-
rotonavir is an antiviral that treats HIV/AIDS
note: OATs and OCTs are important for elimination of the drug
Where are OATs and OCTs commonly localised
on epithelial and endothelial cells
- Regulate solute transport between fluid compartments
- Eg in GI tract, between blood + gut lumen
- Eg in hepatocyte, between blood + bile
- Eg in choroid plexus cell, between blood + CSF
In most cases, what type of transporter are OATs
uptake transporters
So they bring the substrate into the cell
(in most, but not all, cases)
Importance of OATs and OCTs for drug pharmacokinetics + toxicity
- Many drugs are hydrophilic (charged)
- Charged drugs can’t get across lipid bilayer → depend upon carrier mediated transport for absorption, distribution + elimination
- For drugs to reach target, carriers are required at each membrane boundary from site of administration
- Also important for drug elimination (next card)
Drug elimination
- OATs can directly remove drugs (eg penicillin) from the kidney → affects the drug’s therapeutic profile
- Many drugs undergo metabolism by enzymes that increase their charge (so that they can be eliminated by the kidneys). The greater a charge on a metabolised drug, the easier it is for the kidney to excrete it by glomerular filtration or by OATs.
- If 2+ drugs are removed by the same OAT, there can be competition for carriage → change in drug half life. This property can be therapeutically exploited by co-administration of a competitive inhibitor.
Transport of organic anions (OA-) from capillary to proximal tubule lumen (filtrate) of kidney
Na+-K+-ATPase provides an Na+ gradient by
K+ into proximal tubule cell (from capillary) and Na+ into capillary (from PTC)
dicarboxylate transporter is secondary active transport
Uses Na+ gradient to symport dicarboxylate into proximal tubule cell (from capillary) with Na+
OAT1, OAT2, OAT3 act as tertiary active transport
Uses dicarboxylate gradient to antiport OA- into proximal tubule cell (from capillary) and dicarboxylate back into capillary
OA- then transported into proximal tubule lumen (filtrate) by other transporters
Transport of organic cations (OC+) from capillary to proximal tubule lumen (filtrate) of kidney
Note that: pH of capillary is 7.4, lower (more acidic) in proximal tubule cell, and more acidic in the lumen (urine)
OCT2 transports OC+ into proximal tubule cell (from capillary)
☞ the OC+ is attracted into cell as the cell membrane is negatively charged
(therefore by the electrochemical gradient)
MATE1 and MATE2/2-K
These can transport OC+ from the proximal tubule cell into the lumen by antiport of H+ (from urine) into cell
Therefore OC+ transport is driven by the pH gradient
Metformin transport by OCTs
- metformin is the first line drug for treating T2 diabetes
- Has a pleitropic activity, but key site is the liver to decrease hepatic glucose production
- Needs to get in liver (but positively charged) so dependent on OCT transporters (such as OCT1)
- Some patients express variant alleles for OCT1 that reduce OCT1 activity (metformin is less effective → less control over blood glucose)
☞ pleitropic = many different pathways
Cisplatin and OCT2 associated cytotoxicity
cisplatin is a platinum-based chemotherapy agent (disrupts DNA so that cell proliferation is disrupted)
- Kidney damage, hearing loss and sensory neuropathy are common side effects
- Toxicity is due to cisplatin being an excellent OCT2 substrate (so can get into proximal tubule cell)
- However, cisplatin is a poor substrate of either MATE1 or MATE2-K (therefore cannot get out of proximal tubule cell and into urine)
- Cisplatin accumulates in some cells (eg some nerve cells, hair cells of ear) to cause cell death
Cisplatin and OCT2 associated cytotoxicity
cisplatin is a platinum-based chemotherapy agent (disrupts DNA so that cell proliferation is disrupted)
- Kidney damage, hearing loss and sensory neuropathy are common side effects
- Toxicity is due to cisplatin being an excellent OCT2 substrate (so can get into proximal tubule cell)
- However, cisplatin is a poor substrate of either MATE1 or MATE2-K (therefore cannot get out of proximal tubule cell and into urine)
- Cisplatin accumulates in some cells (eg some nerve cells, hair cells of ear) to cause cell death
