Pharmacokinetics and Pharmacodynamics of Ketamine Enantiomers in Surgical Patients Using a Stereoselective Analytical Method

Abstract

In a randomized, double-blind study, we have examined the stereoselective disposition and pharmacodynamic characteristics of ketamine in surgical patients after i.v. administration of S(+)-ketamine 1 mg/kg body weight (25 patients) or racemic ketamine 2 mg/kg body weight (25 patients). S(+)-Ketamine was not inverted to R(-)-ketamine. After racemate administration we observed statistically significant (P < 0.01) smaller clearance and volume of distribution for R(-)-ketamine compared with S(+)-ketamine. In contrast, the pharmacokinetic variables of S(+)-ketamine were not significantly different between treatment groups. Systolic and diastolic arterial pressure and heart rate increased significantly (P < 0.005) in both groups. At 1, 3 and 15 min after S(+)-ketamine administration, significantly greater increase in systolic and diastolic pressures were observed compared with the racemate group. There was no correlation between the changes in haemodynamic variables and plasma catecholamine concentrations, which remained unaffected after administration of the medications.

A parallel chiral–achiral liquid chromatographic method for the determination of the stereoisomers of ketamine and ketamine metabolites in the plasma and urine of patients with complex regional pain syndrome

“…The relative plasma concentrations of (R)-/(S)-Ket and (R)-/(S)-norKet were 1.3 and 1.4, respectively, Fig 2B, which is consistent with data from the previous study where the average (R)-/(S)-Ket and (R)-/(S)-norKet plasma concentrations were 1.1 and 1.2, respectively [1,2]. The relative concentrations reflect the previous reports that there is a significant difference in the plasma clearance of (R)-Ket versus (S)-Ket and that the C max and AUC values for (R)-norKet are greater than those of (S)-norKet [1,2,6,7,10]. The relative plasma concentration of (R)-/(S)-DHNK was 1.4, which represents the first report of the relative enantiomeric plasma concentrations of these compounds in humans after the administration of (R,S)-Ket.…”

“…3B. Since previous studies demonstrated that norKet is hydroxylated at the C4, C5 and C6 positions on the cyclohexanone ring [6,7], the four unknown compounds were identified as HNK metabolites and labeled as compounds 4c, 4d, 4e and 4f . While the structures of 4c – 4f have not been definitively identified, it is possible to make tentative assignments.…”

“…Previously reported enantioselective analytical methods have utilized the α 1 -acid glycoprotein chiral stationary phase, AGP-CSP, to determine the plasma concentrations of (R)- and (S)-Ket and (R)- and (S)-norKet in surgical patients [6] and volunteers [7,8] and a 3,5-dimethyl carbamoylated cellulose CSP, the OD-CSP, to measure the same compounds in the plasma of volunteers receiving (R,S)-Ket via different routes of administration [9,10]. These studies did not measure the other enantiomeric metabolite, (R,S)-DHNK, or the diastereomeric HNK and HKet metabolites.…”

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

“…In our current study, we observed that 0.1–0.3 mM ketamine did not induce complete anesthesia in the embryos and these doses did not alter DA levels. In patients, ketamine plasma sub-anesthetic concentrations range from 0.5–1 µM and anesthesia sets in at ~10–100 µM range (Domino et al, 1982; Geisslinger et al, 1993; Idvall et al, 1979). Our studies on zebrafish embryos treated with 2 mM ketamine that were completely anesthetized (Cuevas et al, 2013) show an internal exposure of ~8 µM (Trickler et al, 2014) and is comparable to the human anesthetic dose range.…”

Ketamine in status asthmaticus: A review

“…[7] Equipotent doses of the S(+)-isomer and the racemate appear to have similar effects on physiologic parameters. [8] There is evidence to suggest that the R(-)-isomer produces a higher rate of emergence reactions and more agitated behavior than the S(+) isomer. [9]…”