PY 6040 GI System

PPIs

Omerprazole is reversible (slowly), pantroprazole is irreversible

Omeprazole
- Interaction with clopidogrel. CYP2C19 activates cloppidogrel. Cant convert the pro-drug into the
usable form if the enzyme is inhibited by omeprazole
- Magnesium, calcium, b-12, iron? Absorption affected.
- Acidity helps suppress bacteria in the gut and the risk of infections goes up if acidity is lowered
- Sulfoxide important in activation.
- Have to be able to draw the arrows to show how the mechanism works. Omeprazole easiest to
remember.
- Cant change the sulfoxide and cant change the CH2. These two groups needed for activity

R/S
- Rate of metabolism is different.
- S form is more affective.

Esomeprazole

Sulfenic acid. important will pick up a proton later = sulfonamide

Sulfenamide- likely to be the active drug. Major electrophile

Slide 36-Active drug is an electrophile that reacts with thiol of cysteine 813.
- Doesnt reach SH822.
- Glutathione can reverse the effect because is doesnt reach the SH822

Slide 39-dusulfide reduction will reverse the effect.

Slide 41
- Ome has two methyl groups and a methoxy group = activates pretty fast. High Pka
- Panto ocf2- pulls electrons from the oxygen, a lot harder to pull the electron= activates slowly.
o Irreversibly inhibits the enzyme
42
- Slow process till we get the active drug

43
- Electrophile comes in closer to sh822 and then covalent bond is formed

47
 - Rabeprazole non enzymatic step involved.
o The product after this step is however CYP2C19 inhibitor.
o

Developments
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