The clinical use of
local anesthetic products to anesthetize mucous membranes has been associated with
methemoglobinemia (MetHba), a serious condition in which the blood has reduced capacity to carry
oxygen. An evaluation of spontaneous adverse event reporting of MetHba submitted to FDA through 2013 identified 375 reports associated with
benzocaine and 16 reports associated with
lidocaine. The current study was performed to determine the relative ability of
benzocaine and
lidocaine to produce
methemoglobin (MetHb) in vitro. Incubation of 500μM
benzocaine with whole human blood and pooled human liver S9 over 5h resulted in MetHb levels equaling 39.8±1.2% of the total
hemoglobin. No MetHb formation was detected for 500μM
lidocaine under the same conditions. Because liver S9 does not readily form
lidocaine hydrolytic metabolites based on xylidine, a primary metabolic pathway, 500μM xylidine was directly incubated with whole blood and S9. Under these conditions MetHb levels of 4.4±0.4% were reached by 5h. Studies with recombinant
cytochrome P450 revealed
benzocaine to be extensively metabolized by
CYP 1A2, with 2B6, 2C19, 2D6, and 2E1 also having activity. We conclude that
benzocaine produces much more MetHb in in vitro systems than
lidocaine or xylidine and that
benzocaine should be more likely to cause MetHba in vivo as well.