Physicochemical properties and cytochromes P-450 kinetics of a trifluoroacetamido derivative of acetaminophen

Abstract

Acetaminophen (N-acetyl-para-aminophenol, APAP) is a commonly used analgesic and antipyretic drug. While acetaminophen is generally safe when taken at therapeutic doses, it causes severe liver and kidney damage at overdose quantities. Cytochromes P-450 (CYP) catalyze the transformation of APAP to N-acetyl-p-benzoquinone imine (NPAQI), a toxic metabolite. The quinone imine moiety of NAPQI reacts with the thiol side chain of glutathione (GSH). High concentrations of NAPQI rapidly deplete cells of GSH resulting in cell death. The introduction of a trifluoromethyl group to APAP would be expected to change the physicochemical properties as well as the kinetics of CYP catalysis of the fluorinated derivative in comparison to APAP. Relative to APAP, 4-triflouroacetamidophenol (3F-APAP) is slightly more acidic and significantly more lipophilic. Using Sprague Dawley rat liver microsomes, it was observed that APAP and 3F-APAP have similar binding affinity for the CYP proteome; however, 3F-APAP undergoes catalysis by the CYP proteome at half the rate as that of APAP. This decreased rate of CYP catalysis for 3F-APAP would be expected to result in it being less hepatotoxic relative to APAP.

Keywords

• Acetaminophen
• Paracetemol
• Fluorine Derivative
• Lipophilicity