Saturable in vitro metabolism of articaine by serum esterases. Does it contribute to the persistence of the local anesthetic effect?
OBJECTIVE
The amide-type local anesthetic articaine is unique in that hydrolysis to articainic acid by serum esterases is its main metabolic pathway. The purpose of the present investigation was to study the concentration dependence of this pathway in vitro.


METHODS
To unbuffered (pH 8.2) as well as phosphate-buffered (pH 7.4) heated serum samples were added various amounts of articaine in the range 10-300 micrograms/mL. Concentrations of articaine and articainic acid were measured by high-performance liquid chromatography after incubating the samples at 37 degrees C for intervals ranging from 5 minutes to 6 hours after addition of articaine.


RESULTS
The in vitro metabolism of articaine was shown to undergo pH-dependent Michaelis-Menten kinetics, indicating saturation at higher substrate concentrations. The Michaelis constant K(m) was determined as 175 micrograms/mL and 22.1 micrograms/mL and the maximum reaction rate Vmax as 2.1 micrograms/mL/min and 0.17 microgram/mL/min at pH 8.2 and pH 7.2, respectively. These results support previous in vivo observations that suggest saturable articaine metabolism, indicated by higher articaine/articainic acid metabolic ratio with higher articaine concentrations in alveolar blood after dental extraction.


CONCLUSIONS
Local saturation of the serum esterases may contribute to the advantageous relationship between persistence of the local anesthetic effect and low systemic toxicity caused by the last systemic elimination of articaine (ie, its wide toxic therapeutic ratio).
Oertel
R
R
Institute of Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Germany.
Berndt
A
A
Kirch
W
W
D000779:Anesthetics, Local / Q000737:chemistry / Q000493:pharmacokinetics*; D002355:Carticaine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004950:Esterases / Q000097:blood*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques
D000779:Anesthetics, Local; C055853:2-carboxyarticaine; D002355:Carticaine; D004950:Esterases