drug transporters

Question 1

why does penicillin have a very low half life?

Answer 1

penicillin has accelerated renal excretion due to transporters

Question 2

when the first chemotherapeutic agents were developed there were issues with multi drug resistant tumours - why was this?

Answer 2

some cancer cells had active transporters to remove drug molecules from the cell

Question 3

what are the 2 superfamilies of transporters we know of ?

Answer 3

ATP binding cassette and solute carrier (SLC)

Question 4

in what ways can transporters help with adme of drugs?

Answer 4

• 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

Question 5

what are some of the atp binding cassette transporters?

Answer 5

pgp mrp and bcrp - these are all efflux pumps - they kick substrates out of the cell

Question 6

what are some of the common solute carrier transporters?

Answer 6

OATPB1, OCT1, OCT2, OAT1, OAT3 - these are all uptake transporters although some efflux sls pumps also exist.

Question 7

how do transporters affect the uptake of organic anions?

Answer 7

uptake occurs by OATP in the intestine and hepatic site and by OAT1 and OAT3 in the kidneys

Question 8

how do transporters affect the uptake of small organic cations?

Answer 8

uptake is by OCT1 in the liver and OCT2 in the kidney

Question 9

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?

Answer 9

tight junctions

Question 10

how does the distribution of pgp in tissue affect drug absorption?

Answer 10

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.

Question 11

what is coexpression?

Answer 11

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.

Question 12

what does the transporter pgp do?

Answer 12

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

Question 13

how can michealis menten kinetics be used to describe the rate of transporters?

Answer 13

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.

Question 14

how can transporters be used as targets for serum urate levels?

Answer 14

probenecid interferes with kidney OAT and inhibits the tubular reabsorptionof urate, increasing the urinary excretion of uric acid and therefore decreasing serum urate levels.

Question 15

how can the activity of OCT1 affect metformin distribution?

Answer 15

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.

Question 16

how could patients on statins be at an increased risk of muscle toxicity (myopathy)?

Answer 16

if patients on statins have reduced activity of hepatic OATP1B1 there will be reduced hepatic elimination and therefore an increased systemic concentration.

Question 17

what can create risks of cholestasis?

Answer 17

inhibition of efflux transporters mediating biliary excretion can lead to hepatic accumulation of substrates and risk of cholestasis.

Question 18

many drugs inhibit or induce transporters creating drug interactions. how does atorvastatin do this?

Answer 18

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

Question 19

what happens if quanidine and loperamide are coadministered?

Answer 19

quanidine inhibits pgp - this means when it is taken with loperamide loperamide is able to cross the blood brain barrier causing respiratory depression.

Question 20

when ddis are discovered what must happen?

Answer 20

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.

Question 21

how may gastrointestinal efflux transporters affect bioavailability?

Answer 21

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.

Question 22

how can uptake transporters in the gi tract be beneficial for drug administration?

Answer 22

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.

Question 23

how might controlled release formulations of L-dopa affect the bioavailability?

Answer 23

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.

Question 24

why might transporters have non linear effects?

Answer 24

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.

Question 25

how does the dosage form affect absorption in the gi tract?

Answer 25

immediate release dosage forms will be absorbed in the duodenum into the blood. where as controlled release formulations will be released further down the intestine , this means when it gets absorbed into cells pgp will kick it out hence lowering the bioavailability.

Question 26

hows the distribution equilibrium ratio determined?

Answer 26

the distribution equilibrium ratio is determined by the weight of simple diffusion, facilitated diffusion and active transporters at the BBB - it evaluates how a drug is likely to distribute in the brain.

Question 27

what can be concluded from the distribution equilibrium ratio?

Answer 27

• if the passive processes are faster than active efflux the drug will be evenly distributed between the blood and the brain.
• if efflux dominates, the drug will be at a much higher concentration in the blood than in the brain - this is a protective mechanism.

Question 28

what determines total renal excretion?

Answer 28

the amount of drug lost in the kidneys through glomerular filtration and tubular secretion with the amount regained through tubular reabsorption.

Question 29

how do transporters affect renal excretion?

Answer 29

• tubular reabsorption can be passive and mediated by transporters
• tubular secretion is always mediated by transporters
  saturation and ddis may occur that would modify renal clearance

Question 30

how may transporters in the bile tract affect drugs?

Answer 30

transporters into the bile duct may rate control hepatic clearance

Question 31

how may transporters in hepatocytes affect drugs?

Answer 31

transporters into hepatocytes may rate control hepatic clearance.

Question 32

how are statins affected by transporters?

Answer 32

statins are hydrophilic molecules that rely on transporters to enter the liver - this is both their site of action and their clearance site.

Question 33

how are atorvastatin and cerivastatin affected by transporters?

Answer 33

atorvastatin and cerivastatin require uptake transporters to enter the liver, they are then metabolised by CYP enzymes.

Question 34

how are pravastatin and rosuvastatin affected by transporters?

Answer 34

pravastatin (a very hydrophilic molecule) and rosuvastatin require uptake transporters to enter the liver, they are also excreted into the bile tract via transporters.

Question 35

how are losuvastatin and simvastatin given?

Answer 35

losuvastatin and simvastatin are given as lipophilic lactone pro drugs which can passively diffuse into the liver where they then form the acid form of the drug. these will then be metabolised by CYP3A and CYP2C8.

Question 36

how may genetic variations affect statins?

Answer 36

genetic variations can affect uptake into the liver. OATP1 facilitates hepatic uptake hence low OATP1 activity may:
- decrease the cholesterol lowering affect as the statins have less access to the liver/site of action
- increase plasma concentration due to reduced hepatic clearance
- increase the risk of muscle toxicity
the impact will vary for different statins and is more marked for those with poor passive permeability.

Question 37

why might it be beneficial to use a prodrug statin?

Answer 37

using a prodrug like the lactone form used for lovastatin and simvastatin means there wont be genetic variability due to OATP1 activity as it will enter the liver via passive diffusion rather than uptak transporters due to their lipophilicity.

Question 38

pravastatin is rapidly orally absorbed, yet why is its F just 18%

Answer 38

pravastatin is greatly affected by stomach degradation and the hepatic first pass effect.

Question 39

explain how the plasma profiles of simvastatin vary when given in the lactone or acid form

Answer 39

when the acid form was given, patients with the genotype c.521cc had a much higher bioavailability (almost toxic) due to the reduced OATP1B1 activity ijn the hepatocytes. however, when given in the lactone form there was no significant variation between genotypes.
the c.521cc genotype is closely associated with simvastatin induced myopathy.

Question 40

how does probenacid affect penicillin?

Answer 40

probenacid inhibits the active tubular secretion of penicillin at the kidney, increasing the half life.

Question 41

how does fruit juice affect transporters?

Answer 41

some fruit juices may inhibit OATP1A2 like apple orange and grapefruit

Question 42

how does rifampicin affect other drugs?

Answer 42

rifampicin induces pgp causing reduced oral absoprtion of substrates like cyclosporine and tacrolimus, this means they have a lower F and reach sub therapeutic levels

Question 43

what ddis does st johns wort have?

Answer 43

st johns wort induces pgp hence reducing the oral absorption of digoxin so it has a reduced f.

Question 44

what are some other inhibitors of pgp that may lead to increased oral absorption of digoxin?

Answer 44

itraconaxole, ketoconazole and ritonavir all inhibit pgp.

Question 45

pgp and cyp3a4 overlap extensively on substrates, inducers and inhibitors, what does this mean for rifampicin?

Answer 45

not only does rifampicin induce pgp but it also induces cyp3a4

Question 46

how does grapefruit juice effect drugs?

Answer 46

grapefruit juice inhibits pgp and some oatps - this alters the pharmacokinetices of cyclosporine and fexofenadine.