DILI: APAP PK/PD

Question 1

APAP absorption rate

Answer 1

Rapid PO absorption

Question 2

In an APAP OD, what happens to APAP.absorption?

Answer 2

It still mostly occurs within 2 hours with complete absorption by hour 4

Question 3

Where does APAP cross?

Answer 3

BBB and placenta

Question 4

25% of APAP is extracted where?

Answer 4

1st pass metabolism

Question 5

Where is the other 75% of APAP metabolized?

Answer 5

90% of that 75% goes through hepatic conjugation via glucuronidation and sulfation

<5% eliminated unchanged in urine

5-15% oxidized by CYP2E1 to NAPQI

Question 6

In APAP OD, what happens to APAP glucuronidation and sulfation?

Answer 6

The pathways become saturated and shunts more metabolism towards the 2E1 pathway and produces more NAPQI

Question 7

In normal situations, what happens to the toxic NAPQI?

Answer 7

Combines rapidly with glutathione (free radical scavenger in the body) and converted to nontoxic cysteine or mercaptate conjugates which can be eliminated in the urine

Question 8

In APAP OD, what happens to the toxic NAPQI?

Answer 8

Glutathione stores are eventually diminished and can’t regenerate fast enough → NAPQI begins attacking hepatocytes, setting off a chain of events → hepatocyte injury and death