Background and Objectives 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 μg/mL. Concentrations of articaine and articainic acid were measured by high-performance liquid chromatography after incubating the samples at 37°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 Km was determined as 175 μg/mL and 22.1 μg/mL and the maximum reaction rate Vmax as 2.1 μg/mL/min and 0.17 μg/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.
Conclusion 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 fast systemic elimination of articaine (ie, its wide toxic therapeutic ratio).
- local anesthetics
- Michaelis-Menten kinetics
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Study was supported by Hoechst AG, Hoechst Pharma, Deutchland.
Presented in part as a poster at the 36th Spring Meeting of the Deutsche Gesellschaft für Pharmakologie und Toxikologie, Mainz, March 14-16, 1995.