Clinical Pharmacology and Therapeutics

30 DRUG METABOLISM
Case history
A 46-year-old woman is brought to the hospital Accident
and Emergency Department by her sister, having swallowed
an unknown number of paracetamol tablets washed
down with vodka six hours previously, following an argument
with her partner. She is an alcoholic and has been
taking St John’s wort for several weeks. Apart from signs
of intoxication, examination was unremarkable. Plasma
paracetamol concentration was 662 μmol/L (100 mg/L).
Following discussion with the resident medical officer/
Poisons Information Service, it was decided to administer
N-acetylcysteine.
Comment
In paracetamol overdose, the usual pathway of elimination
is overwhelmed and a highly toxic product (N-acetyl benzoquinone
imine, known as NABQI) is formed by CYP1A2, 2E1
and CYP3A4 metabolism. A plasma paracetamol concentration
of 100 mg/L six hours after ingestion would not usually
require antidote treatment, but this woman is an alcoholic
and is taking St John’s wort and her hepatic drugmetabolizing
enzymes (CYP1A2, CYP3A4 and probably
others) will have been induced, so the paracetamol concentration
threshold for antidote treatment is lowered (see
Chapter 54). N-Acetylcysteine is the specific antidote, as it
increases reduced glutathione which conjugates NABQI
within hepatocytes.
FURTHER READING AND WEB MATERIAL
Boobis AR, Edwards RJ, Adams DA, Davies DS. Dissecting the function
of P450. British Journal of Clinical Pharmacology 1996; 42: 81–9.
Coon MJ. Cytochrome P450: nature’s most versatile biological catalyst.
Annual Review of Pharmacology and Toxicology 2005; 45: 1–25.
Lin JH, Lu AY. Interindividual variability in inhibition and induction
of cytochrome P450 enzymes. Annual Review of Pharmacology and
Toxicology 2001; 41: 535–67.
Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert
DW. Comparison of cytochrome P450 (CYP) genes from the
mouse and human genomes, including nomenclature recommendations
for genes, pseudogenes and alternative-splice variants.
Pharmacogenetics 2004; 14: 1–18.
Website for CYP450 substrates, inhibitors and inducers:
www.medicine.iupui.edu/flockhart/table, accessed April 2007.