drug transporters Flashcards
why does penicillin have a very low half life?
penicillin has accelerated renal excretion due to transporters
when the first chemotherapeutic agents were developed there were issues with multi drug resistant tumours - why was this?
some cancer cells had active transporters to remove drug molecules from the cell
what are the 2 superfamilies of transporters we know of ?
ATP binding cassette and solute carrier (SLC)
in what ways can transporters help with adme of drugs?
- help absorption into the blood from the intestines
- helps with hepatic clearance from the blood and liver
- helps protect the brain by controlling distribution - BBB stops drug from the blood entering the brain
- helps drug be renally cleared from the blood
what are some of the atp binding cassette transporters?
pgp mrp and bcrp - these are all efflux pumps - they kick substrates out of the cell
what are some of the common solute carrier transporters?
OATPB1, OCT1, OCT2, OAT1, OAT3 - these are all uptake transporters although some efflux sls pumps also exist.
how do transporters affect the uptake of organic anions?
uptake occurs by OATP in the intestine and hepatic site and by OAT1 and OAT3 in the kidneys
how do transporters affect the uptake of small organic cations?
uptake is by OCT1 in the liver and OCT2 in the kidney
transporters need to be orientated and distributed on the specific membranes of the cell (apical or basolateral) - what helps transporters stay on the correct membrane?
tight junctions
how does the distribution of pgp in tissue affect drug absorption?
pgp is more expressed in distal (ileum) parts of the small intestine compared to the proximal part (duodenum). this therefore effects the exposure of drugs to pgp. highly soluble and permeable drugs will be rapidly absorbed in the duodenum with little exposure to pgp. this means drugs in slow release formulations will have more exposure to pgp.
what is coexpression?
some transporters are coexpressed with metabolic enzymes. this is a good mechanism from endogenous substances as the transporters can remove drugsfrom cells whilst enzymes can metabolise any which are not substrates of the transporter.
what does the transporter pgp do?
pgp always effluxes substrates into the lumen of the organ where it is expressed.
- pgp in the enterocytes of the intestine remove drug from the blood lowerinf its bioavailability
- pgp in hepatocytes and proximal tubiule cells of the kidney increase clearance of the drug
- pgp in the bbb decreases the distribution of drugs into the brain
- pgp in the placenta protects the foetus from harmful substances
pgpp has a broad range of substrates
how can michealis menten kinetics be used to describe the rate of transporters?
at first the rate of transport is directly proportional to the concentration of the substrate until the transporters get saturated at which point the rate of transport will reach a maximum and constant body.
how can transporters be used as targets for serum urate levels?
probenecid interferes with kidney OAT and inhibits the tubular reabsorptionof urate, increasing the urinary excretion of uric acid and therefore decreasing serum urate levels.
how can the activity of OCT1 affect metformin distribution?
patients with reduced OCT1 activity will have a decreased hepatic uptake of metformin so there will be a reduced response. however this will not impact the elimination of metformin as it is predominantly renally excreted.
how could patients on statins be at an increased risk of muscle toxicity (myopathy)?
if patients on statins have reduced activity of hepatic OATP1B1 there will be reduced hepatic elimination and therefore an increased systemic concentration.
what can create risks of cholestasis?
inhibition of efflux transporters mediating biliary excretion can lead to hepatic accumulation of substrates and risk of cholestasis.
many drugs inhibit or induce transporters creating drug interactions. how does atorvastatin do this?
atorvastatin is a substrate for OATPs and pgp and primarily metabolised by the enzyme CYP3A4. it therefore has drug interactions when given with transporter or metabolism inhibitors
what happens if quanidine and loperamide are coadministered?
quanidine inhibits pgp - this means when it is taken with loperamide loperamide is able to cross the blood brain barrier causing respiratory depression.
when ddis are discovered what must happen?
we must change labels and produce warnings when a new ddi is discoverres with clinical consequences. we may also need to reevaluate the mechanism of action of drugs believed to be metabolism based only.
how may gastrointestinal efflux transporters affect bioavailability?
efflux transporters in the gi tract may reduce the bioavaialbility of some drugs as they reduce the amount reaching systemic circulation, this can occur to drugs that even have good passive permeability.
how can uptake transporters in the gi tract be beneficial for drug administration?
gastrointestinal uptake transporters may enable the oral administration of drugs with poor passive permeability like amoxicillin and l-dopa. however the gastrointestinal uptake transporters are located at the beginning of the small intestine (the absorption window) hece the drug must be released from the formulation by this point in order to be absorbed at the transporter site. this can be challenginf for slow release formulations.
how might controlled release formulations of L-dopa affect the bioavailability?
as l dopa has poor passive permeability the absorption relies on uptake transporters loacted at the proximal end of the intestines. this therefore means that l dopa released at the beginning of the intestine will be absorbed whilst any drug released from the formulation beyond the absorption window will not be absorbed as it will be too far down the gi tract so there will no longer be uptake transporters to help the absorption process. you can see this effect with sinemet CR and madopar CR - these are controlled release formulations and have a F of 30-40% less than the non-controlled release form.
why might transporters have non linear effects?
the gastrointestinal efflux and uptake pumps may become saturated hence they would have nonlinear effects as the AUC and Cmax will not proportionally increase with dose and the fraction absorbed will not be constant.
