2005B01 Describe how isoflurane is metabolized. In your answer give reasons
why the overall extent of metabolism of isoflurane is so low.

Physicochemical

·  H: ↑flammable

·  F: ↓flammable

·  CHF₂ + dry sodalime -> carbon monoxide

Pharmacokinetic

·  C-F: resistant to oxidative metabolism -> ↓toxicity

Pharmacodynamic

·  H: ↑potent

·  F: ↓potent

·  Cl: ↓potent

Proportion

·  Only 0.2%

o Low solubility

o Many C-F groups -> resistance to metabolism

o Readily excreted by the lungs -> less opportunity for metabolism

Location

·  Liver

Mode

·  Phase 1: mostly CYP2E1

Metabolites

·  Trifluoroacetic acid

·  Fluoride

Excretion

·  Lungs

Toxicity rare

In theory:

·  Hepatotoxicity: antibody binds TFA (hapten) + hepatic proteins

·  Nephrotoxicity: free fluoride -> high output renal failure