These results show that coxibs do reach the CNS in humans, with rapid penetration, and in concentrations apparently sufficient to inhibit COX-2 activity. There were significant differences among coxibs in CSF penetration. Unbound (free) plasma coxib concentration was the major determinant of CSF concentration. This supports the hypothesis that coxibs may act, in part, in the human CNS, provide important new information on the mechanism and treatment of pain and may guide coxib selection for therapeutic trials when CNS penetration is desirable.

Fluoride from methoxyflurane anesthesia derives from O-demethylation. Phenobarbital increases in methoxyflurane toxicity do not seem attributable to methoxyflurane dechlorination, MDFA toxicity, or MDFA metabolism to another toxic metabolite, suggesting that nephrotoxicity is attributable to methoxyflurane O-demethylation. Fluoride, one of many metabolites from O-demethylation, may be toxic and/or reflect formation of a different toxic metabolite. These results may have implications for interpreting anesthetic defluorination, volatile anesthetic use, and methods to evaluate anesthetic toxicity.