DDIs

Question 1

give an example of a drug which was removed from the market because of severe DDIs?

Answer 1

cerivastatin

Question 2

how can we classify CYP inhibitors?

Answer 2

strong: 5 fold increase in AUC
moderate: 2 - 5 fold increase in AUC
weak: 1.25 - 2 fold increase in AUC

Question 3

smoking and clozapine?

Answer 3

smoking induces CYP1A2 so when given with clozapine, the plasma conc decreases of clozapine so increased CL

Question 4

what are the 2 subfamilies of transporters?

Answer 4

ATP binding cassettes (ABC)
solute carrier (SLC)

Question 5

where are most transporters found?

Answer 5

epithelia of intestine, liver and kidney

endothelium of bbb

Question 6

why is it key that statins are taken up by transporter OATP1B1 rather than stay in plasma?

Answer 6

bcos need to be in the liver to have its therapeutic effect, no point being in plasma
they take the statin up in acidic form though which is it what the prodrug turns into (from a lactone)

Question 7

what does OATP1B1 take up compared to OATP1B3?

Answer 7

B1 is statins, valsartan and also bile acids and bilirubin

B3 is similar to B1 but also glutathione and is found in cancer tissues

Question 8

give a drug that is an inhibitor of OATP1B1?

Answer 8

Ciclosporin

Question 9

P-gp DDIs are common with which drug?

Answer 9

digoxin as has very narrow TW

Question 10

what in-vivo methods are there to investigate risk of transporter DDIs?

Answer 10

• clinical studies with cocktails of drug transporter probes
• endogenous biomarkers e.g. bile as this is a substrate for transporters but needs to be selective and sensitive
• use of pre-clinical species like cynomolgus monkey
• PET imaging