Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats

• Blood-plasma partitioning of (R,S)-DHNK in rats.
• Acute versus subchronic administration of Ket.
• Subchronic administration of (R,S)-Ket results in a different metabolite pattern.

Subchronic administration of (R,S)-ketamine, (R,S)-Ket, is used in the treatment of neuropathic pain, in particular Complex Regional Pain Syndrome, but the effect of this protocol on the metabolism of (R,S)-Ket is unknown. In this study, daily administration of a low dose of (R,S)-Ket for 14-days to Wistar rats was conducted to determine the impact of sub-chronic dosing on the pharmacokinetics of (R,S)-Ket and its major metabolites. The data indicate that, relative to a single administration of (R,S)-Ket, subchronic administration resulted in increased clearance of (R,S)-Ket and the N-demethylated metabolite norketamine measured as elimination half-life (t1/2) and decreased plasma concentrations of these compounds. Subchronic administration produced a slight decrease in t1/2 and an increase in plasma concentration of the major metabolite, (2S,6S;2R,6R)-hydroxynorketamine, and produced significant increases in the plasma concentrations of the (2S,6R;2R,6S)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine metabolites. The metabolism of (R,S)-Ket predominately occurs via two microsomal enzyme-mediated pathways: (R,S)-Ket ⇒ (R,S)-norketamine ⇒ (2S,6S;2R,6R)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine and the (R,S)-Ket ⇒ (2S,6R;2R,6S)-hydroxyketamine ⇒ (2S,6R;2R,6S)-hydroxynorketamine and (2S,6S;2R,6R)-hydroxynorketamine. The results indicate that the activity of both metabolic pathways are increased by subchronic administration of (R,S)-Ket producing new metabolite patterns and potential differences in clinical effects.