Elimination

Question 1

Define Irinotecan toxicity in relation to SNPs of UGT1A1.

Answer 1

Irinotecan = colorectacl cancer drug

• Activation by hydrolysis turns irinotecan into toxic SN-38
• UGT1A1 then deactivates SN-38 to SN-38G which is not toxic

28* variant homozygotes have less SN-38 conjugation to SN-38G and experience irinotecan toxicity

Question 2

Describe variance in alleles between ethnicities.

Answer 2

Allelic variants are more prominent in some ethnic groups and that this means that there is a greater chance of an altered phenotype in that population (but NOT that all individuals from that population will carry that polymorphism).

Question 3

Describe the ABC transporter mechanism.

Answer 3

ABC transporter mechanism

• ABC transporters exist in the membrane as dimers
• In the open dimer form the transporter accepts substrate (inside cell)
• Binding of ATP produces a conformational shift
• The substrate is effluxed and ATP is dephosphorylated to produce ADP
• The starting conformation is restored to accept further substrate present in the cell

Question 4

Describe the modes of Renal Elimination.

Answer 4

Glomerular filtration
o Removal of free drug (not bound to plasma proteins) at the glomerulus

Active tubular secretion
o Drug is transported from blood into urine by tubular transporter proteins

Tubular reabsorption
o Passive process in which drug in urine diffuses back into blood
o favours unionised drug
o Therefore, urinary pH important

Question 5

Describe the two mechanisms in which drugs can appear in faeces.

Answer 5

1. By not being absorbed into the systemic circulation – so drug passes along the intestine
2. By being absorbed, excreted in bile and then – Being deposited back into the intestine