Session 3.4: Organic Anion and Cation transporters: importance in drug metabolism

Question 1

what are organic anion transporters

Answer 1

poly-specific anionic substrate transporters

expressed in many tissues

Question 2

what is the purpose of organic anion transporters

Answer 2

mediated uptake and transport of organic anions

can transport natural substrates or common drugs

Question 3

what is the function of renal organic anion transporter

Answer 3

pick up anions from circulation and transport into kidney, in exchange for dicarboxylate ions through a dicarboxylate transporter which is driven by the inward sodium gradient of the cell created by sodium-potassium ATPase. dicarboxylate can then exchange for other anions uptake
the organic anions can be excreted into filtrate through ABC cassette proteins or multidrug resistance protein

Question 4

what is organic anion transporter 1/3 driven by

Answer 4

alpha ketoglutarate

Question 5

what is organic anion transporter 2 driven by

Answer 5

succinate

Question 6

what is the function of organic anion transporters

Answer 6

regulates levels of key metabolites and signalling molecules - important in homeostais
inter-organ communication
inter-organismal communication via movement of small molecules across the intestine, breast milk, placental barrier, volatile odorants into the urine

Question 7

what are organic cation transporters

Answer 7

poly-specific cationic substrate transporters eg: dopamine, serotonin, histamine
expressed in many tissues

Question 8

what is the function of organic cation transporters

Answer 8

terminate signalling molecules in tissues

Question 9

what is the function of renal organic cation transporter

Answer 9

mediated uptake and transport of organic cations

Question 10

how does renal organic cation cotransport work

Answer 10

cations in blood picked up by OCT2 into proximal tubule cell which is driven by electrochemical gradient which can then pass into filtrate/urine as driven by pH gradient, hydrogen ion gradient inwards through MATE 1 and 2

Question 11

what should organic cations be considered when thinking about

Answer 11

dosage level - as positively charged drugs exit before reaching target tissue

Question 12

what are organic cation transporters driven by

Answer 12

negative membrane potential

Question 13

what are multidrug and toxin extrusion proteins 1-2 driven by

Answer 13

pH gradient

Question 14

what are some examples of drug substartes affected by organic cation activtiy

Answer 14

amiloride - hypertension
atenolol - angina
cisplatin - cancers
liodocaine - anaesthetic
metformin - type 2 diabetes
rotonavir - hiv/aids

Question 15

why might organic cation transports affect drug availability

Answer 15

metformin - causes decreased heptatic glucose production
some patients may have reduced activity of their OCT1 so hepatic uptake of metformin reduced - less effective - glucose levels high

Question 16

how might organic transporters cause toxic drug accumulation

Answer 16

cisplatin - taken up by OCT2 into cells - good for cancer. but in kidney also enters proximal tubule cells, and MATE1/2 has low affinity so not being excreted into urine resulting in nephrotoxicity - reduces maximal therapeutic dosing - conscious about possible damage