Tissue uptake of ketamine and norketamine enantiomers in the rat: indirect evidence for extrahepatic metabolic inversion.

Ketamine, used clinically as an intravenous analgetic and dissociative anaesthetic agent, is a racemate with both pharmacokinetic and pharmacodynamic enantioselectivity. S-ketamine has been found have a higher clearance and greater potency than R-ketamine as well as a greater therapeutic index. We performed a study in rats with two complementary paradigms: (i) constant rate "washin" infusion until fatal, (ii) brief infusion then "washout". These, respectively, allowed examination of ketamine and norketamine serial plasma enantiomer concentrations and tissue distribution at maximal and minimal drug effects. Both paradigms found plasma concentrations of R-ketamine>S-ketamine; however, tissue distribution coefficients for S-ketamine>R-ketamine. For paradigm (i), plasma concentrations of R-norketamine>S-norketamine; for paradigm (ii), R-norketamine>>S-norketamine initially, but S-norketamine>>R-norketamine later. Comparison of distribution coefficients of ketamine and norketamine enantiomers for the two paradigms provided indirect evidence for metabolic inversion. During washin, when circulating concentrations of ketamine enantiomers were high, uptake and metabolism occurred predominantly in the kidney and to a lesser extent in liver, lung and gut, with formation of R-norketamine by a (presumed) first-order process predominating. However, following washout, when circulating concentrations of ketamine enantiomers were low, uptake and metabolism was dominated by the kidney and gut. Under these conditions inversion of R- to S-ketamine appeared to predominate with subsequent metabolism to S-norketamine by (presumed) zero-order processes. In summary, different profiles for the uptake and metabolism of ketamine enantiomers were apparent following constant rate washin, and brief infusion washout, paradigms with i.v. rac-ketamine. Uptake into most tissues, and metabolism in some tissues, was enantioselective.