The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats

The distribution, clearance, and bioavailability of (2S,6S)‐hydroxynorketamine has been studied in the Wistar rat. The plasma and brain tissue concentrations over time of (2S,6S)‐hydroxynorketamine were determined after intravenous (20 mg/kg) and oral (20 mg/kg) administration of (2S,6S)‐hydroxynorketamine (n = 3). After intravenous administration, the pharmacokinetic parameters were estimated using noncompartmental analysis and the half‐life of drug elimination during the terminal phase (t1/2) was 8.0 ± 4.0 h and the apparent volume of distribution (Vd) was 7352 ± 736 mL/kg, clearance (Cl) was 704 ± 139 mL/h per kg, and the bioavailability was 46.3%. Significant concentrations of (2S,6S)‐hydroxynorketamine were measured in brain tissues at 10 min after intravenous administration, ~30 μg/mL per g tissue which decreased to 6 μg/mL per g tissue at 60 min. The plasma and brain concentrations of (2S,6S)‐hydroxynorketamine were also determined after the intravenous administration of (S)‐ketamine, where significant plasma and brain tissue concentrations of (2S,6S)‐hydroxynorketamine were observed 10 min after administration. The (S)‐ketamine metabolites (S)‐norketamine, (S)‐dehydronorketamine, (2S,6R)‐hydroxynorketamine, (2S,5S)‐hydroxynorketamine and (2S,4S)‐hydroxynorketamine were also detected in both plasma and brain tissue. The enantioselectivity of the conversion of (S)‐ketamine and (R)‐ketamine to the respective (2,6)‐hydroxynorketamine metabolites was also investigated over the first 60 min after intravenous administration. (S)‐Ketamine produced significantly greater plasma and brain tissue concentrations of (2S,6S)‐hydroxynorketamine relative to the (2R,6R)‐hydroxynorketamine observed after the administration of (R)‐ketamine. However, the relative brain tissue: plasma concentrations of the enantiomeric (2,6)‐hydroxynorketamine metabolites were not significantly different indicating that the penetration of the metabolite is not enantioselective.