Received for publication December 4, 2007.
Revised May 14, 2008.
Accepted for publication May 14, 2008.

Assessment of the Medicines Lidocaine, Prilocaine and Their Metabolites, 2,6-Dimethylaniline and 2-Methylaniline, for DNA Adduct Formation in Rat Tissues

Abstract

The local anesthetics lidocaine (lido, 2,6-xylidine) and prilocaine (prilo, o-toluidine) are metabolized to their constituent aromatic amines 2,6-dimethylaniline (DMA) and 2-methylaniline (MA), respectively, which are both tumorigenic in rats. The capacity of lido and prilo to form DNA adducts was assessed in major target tissues for aromatic amines in male F344 rats in comparison to equimolar quantities of DMA and MA using the ³²P-postlabeling assay. Direct reaction of putative DNA-reactive metabolites N-hydroxy-DMA and N-hydroxy-MA with isolated DNA yielded reference adducts. Rats were dosed by oral gavage with 0.5 mmole/kg bw of each test substance or the vehicle either once or daily for 7 days. After repeat administrations of either prilo or lido, DNA adducts were detected in the liver and nasal mucosa. Urinary bladder DNA adducts were detected only in lido and DMA multi-dose treated rats. Groups dosed with DMA or MA showed adducts in both single and multiple dose groups, except for the single dose DMA liver and urinary bladder samples which were below the level of detection. No DNA adducts were detected in any of the white blood cells samples under either dosing regimen. The lido- and prilo-DNA adducts detected were chromatographically indistinguishable from those formed either in DMA- or MA-dosed rats, respectively, or by chemical reaction of the corresponding N-hydroxy derivatives with DNA. Thus, lido and prilo can generate DNA adducts in rats via their aromatic amine metabolites, although at lower levels than equal molar quantities of their amine metabolites

Key words: anesthetics, bioactivation, chemical carcinogenesis, covalent drug binding, DNA adducts, DNA binding, drug toxicity, genotoxicity, reactive metabolites, safety evaluation