Ketamine kinetics in unmedicated and diazepam-premedicated subjects

Abstract

Plasma ketamine concentrations after diazepam and placebo pretreatment were examined in a double-blind, randomized, cross-over study. Eight healthy male subjects received either diazepam or a 0.9% NaCl placebo before ketamine and received the alternate combination 5 to 24 days later. Ten minutes before ketamine dosing, diazepam, 0.3 mg/kg, or placebo in equal volume was injected intravenously at a rate not exceeding 5 mg/min. Ketamine, 2.2 mg/kg iv, was injected over 1 min. For the clinically relevant period for anesthesia (1 to 30 min), diazepam-ketamine treatment resulted in higher plasma levels at most time points, but diazepam pretreatment did not alter plasma levels of metabolite KI and pseudometabolite KII nor the 24-hr urinary excretion of ketamine, KI, and KII. Ketamine kinetics followed a three-term exponential decline under both treatment conditions. After placebo-ketamine dosing, plasma t 1/2s were as follows: distribution (pi t 1/2) = 24.1 sec, redistribution (alpha t 1/2) = 4.68 min, and elimination (beta t 1/2) = 2.17 hr. After diazepam-ketamine dosing, t 1/2s were: pi t 1/2 = 25.0 sec, alpha t 1/2 6.37 min, and beta t 1/2 = 2.32 hr.

Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?

“…The Stanpump program utilizes a "BET" (bolus-elimination-transfer) infusion scheme to attain a steady-state plasma concentration nearly instantaneously, by combining a bolus, a constant rate infusion to compensate for drug elimination, and an exponentially decreasing infusion to compensate for drug distribution or transfer (Kruger-Theimer 1968). Pharmacokinetic parameters for ketamine were taken from a previous study (Domino et al 1984). The target concentrations were designed to approximate the range of concentrations hypothetically achieved by the low and high doses infused in the Krystal et al (1994) and Malhotra et al (1996) studies; the total dose of ketamine infused was 0.97 mg/kg over 2 h. Ketamine plasma concentrations were determined by gas chromatography mass spectrometry (Kharasch and Labroo 1992).…”

General and emotion-specific neural effects of ketamine during emotional memory formation

“…The infusion protocol adhered a previously validated continuous bolus infusion protocol based on a three compartment model (Domino et al, 1982;Schmechtig et al, 2013) and was implemented using the STANPUMP software (Steven L. Shafer, M.D., Anesthesiology Service (112A), PAVAMC, Palo Alto, CA, USA). Ketamine reaches peak plasma concentrations within a minute when administered intravenously (Domino et al, 1984). Ketamine has a high lipid solubility and low plasma protein binding (12%), which facilitates rapid transfer across the blood-brain barrier.…”

The incidence of unpleasant dreams after sub-anaesthetic ketamine

“…Ketamine infusion was via a Graseby intravenous infusion pump controlled by the Stanpump programme (Schafer et al 1990). The programme uses a bolus-elimination-transfer (BET) infusion scheme which aims to achieve the target plasma concentration almost instantaneously by taking into account ketamine pharmacokinetics using a three-compartment model (Domino et al 1984). Participants received either ketamine (low-dose or high-dose) or placebo (0.9% NaCl solution).…”