Stereoselective pharmacokinetics of ketamine:R(−)-ketamine inhibits the elimination ofS(+)-ketamine

Objective We investigated the pharmacokinetics of ketamine with special regard to enantiomer‐specific differences. Methods Ten healthy young male volunteers (mean age, 28 ± 4 years; mean weight, 79 ± 11 kg) received racemic ketamine and S (+)‐ketamine in a randomized double‐blind crossover study. Drugs were administered by a computer‐controlled device. Two infusion cycles with linearly increasing targets [slope, 0.1 μg · ml −1 · min −1 for S (+)‐ketamine and 0.2 μg · ml −1 · min −1 for racemic ketamine] were administered. Concentrations of the ketamine enantiomers were determined from arterial blood, and pharmacokinetic parameters were estimated with a 2‐ and 3‐compartment model. Results The total doses needed to reach defined end points were 271 ± 80 mg and 409 ± 75 mg for S (+)‐ketamine and racemic ketamine, respectively ( P < .05). S (+)‐ketamine showed a significantly higher clearance (26.3 ± 3.5 ml · kg −1 · min −1 ) compared with racemic ketamine (14.8 ±1.7 ml · kg −1 · min −1 ; P < .05) and R (−)‐ketamine (13.8 ±1.3 ml · kg −1 · min −1 ; P < .05). Furthermore, the clearance of the S (+)‐ketamine was smaller in the racemate (18.5 ±0.7 ml · kg −1 · min −1 ; P < .05) than for the pure isomer. Conclusions These results demonstrate that R (−)‐ketamine inhibits the elimination of S (+)‐ketamine. Clinical Pharmacology & Therapeutics (2001) 70 , 431–438; doi: 10.1016/S0009‐9236(01)06321‐4