Mutual inversion of flurbiprofen enantiomers in various rat and mouse strains

Area of Science:

• Pharmacology
• Drug Metabolism
• Chiral Chemistry

Background:

• Flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), is administered as a racemic mixture of R- and S-enantiomers.
• Chiral inversion, the conversion of R- to S-enantiomers, is a significant metabolic pathway for some NSAIDs.
• The enzyme α-methylacyl-CoA racemase (AMACR) is implicated in the chiral inversion of 2-arylpropionic acid NSAIDs.

Purpose of the Study:

• To investigate the chiral inversion of flurbiprofen enantiomers in different animal models.
• To determine the role of AMACR in flurbiprofen's R- to S-enantiomer inversion.
• To assess the suitability of mice and rats as models for human flurbiprofen enantiomer metabolism.

Main Methods:

• Administration of (R)-flurbiprofen (RF) to C57Bl/6 mice, SJL mice, AMACR-deficient mice, Dark Agouti rats, and Lewis rats.
• Quantification of (S)-flurbiprofen (SF) formation to determine the fraction inverted (F_I).
• Comparison of inversion rates across species and in the context of AMACR deficiency.

Main Results:

• C57Bl/6 mice (F_I = 37.7%) and SJL mice (F_I = 24.7%) showed significant R- to S-inversion of flurbiprofen.
• AMACR-deficient mice exhibited no measurable conversion of RF to SF.
• Dark Agouti rats (F_I = 1.4%) and Lewis rats (F_I = 4.1%) demonstrated very low chiral inversion, consistent with previous findings in Sprague-Dawley rats (<5%).

Conclusions:

• AMACR plays a crucial role in the chiral inversion of flurbiprofen from the R- to the S-enantiomer.
• Rats are a more appropriate preclinical model than mice for studying flurbiprofen enantiomers due to their negligible chiral inversion.
• The metabolic profile of flurbiprofen enantiomers in rats closely mimics that observed in humans, where R- to S-inversion is minimal.