title: More methemoglobin is produced by benzocaine treatment than lidocaine treatment in human in vitro systems.
abstract: 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.
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA. Electronic address: neil.hartman@fda.hhs.gov.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hartman
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Jinzhe J
authors.initials: JJ
authors.lastname: Mao
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Division of Pharmaceutical Analysis, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Boyne
authors.affiliation: Division of Anesthesia, Analgesia and Addiction Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Wasserman
authors.affiliation: Division of Medication Error Prevention and Analysis, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Kellie
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Division of Anesthesia, Analgesia and Addiction Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Racoosin
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Patel
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Colatsky
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism / Q000633:toxicity*; D000814:Aniline Compounds / Q000378:metabolism; D001566:Benzocaine / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008012:Lidocaine / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000378:metabolism; D008706:Methemoglobin / Q000378:metabolism; D008708:Methemoglobinemia / Q000139:chemically induced*
chemical_list: D000779:Anesthetics, Local; D000814:Aniline Compounds; C007766:2,6-xylidine; D008706:Methemoglobin; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; D001566:Benzocaine
keywords: Benzocaine; Benzocaine hydroxylamine; Lidocaine; Methemoglobin; Methemoglobinemia; Xylidine