PubMed · 14764199
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N E Diamant. 2004. Mice and methods.. https://doi.org/10.1111/j.1365-2982.2003.00492.x
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Propofol (2,6-diisopropyl phenol) is widely used for the induction and maintenance of anesthesia. Analyses of its pharmacokinetics require simple and sensitive methods for quantitation of propofol in human plasma. Previously reported HPLC and GC methods are limited by cumbersome extraction steps. We describe a novel method that combines sample preparation by solid-phase extraction (SPE) with hydrophilic-lipophilic balance cartridges and analysis with a sensitive LC-APCI-triple quadrupole mass spectrometry (MS/MS) method for better quantitation. The absolute recovery of the analyte was greater than 96%. The limit of quantification for propofol in plasma at a signal-to-noise ratio of 10 was 5 ng/ml. The precision of the assay yielded coefficients of variation ranging from 2.9 to 5.3% and an accuracies of 99-105%. Our method advances the quantitative analysis of propofol in human plasma by combining simple, rapid and efficient SPE with specific and sensitive quantitation by HPLC with APCI-MS/MS detection.
BACKGROUND: Propofol (2,6-diisopropylphenol) is a widely used general anaesthetic that modulates gamma-aminobutyric acid type A (GABA(A)) receptors, the major inhibitory neurotransmitter receptor in the brain. Previous studies have found that the concentration of propofol that is required to affect synaptic inhibition in brain slices is much higher than the free concentration that is achieved clinically and that modulates isolated receptors. We tested whether this is accounted for by slow equilibration in brain tissue, and determined the concentration that must be applied to achieve appropriate brain levels. METHODS: Rat brain slices 300-microm thick were placed in a solution of 100 microM propofol in artificial cerebrospinal fluid for times ranging from 7.5 to 480 min. Concentrations in these slices were measured by HPLC to determine diffusion and partition coefficients. Electrophysiological measurements of the rate at which effects of 5 microM propofol developed were compared with the calculated rate of increase in tissue concentration. RESULTS: The diffusion coefficient was approximately 0.02x10(-6) cm2 s(-1), and the brain:artificial cerebrospinal fluid partition coefficient was 36. Diffusion times in brain slices agreed well with time course measurements of propofol-induced depression of synaptic responses, which continued to increase over 5 h. This depression was reversed by blocking GABA inhibition with picrotoxin (100 microM). CONCLUSIONS: Propofol does enhance inhibition in brain slices at a concentration of 0.63 microM in the superfusate, which produces brain concentrations corresponding with those achieved in vivo, but equilibration requires several hours. It is likely that slow diffusion to GABA receptors accounts for the high concentrations (>10 microM) that were needed to depress evoked responses in previous investigations.
OBJECTIVE: Propofol (2,6-diisopropylphenol) is widely used for anesthetic induction as well as for chronic sedation in intensive care units. In this study, we investigated the interaction between propofol and premedications, i.e., psychotropic and antianxiety agents (diazepam, midazolam), hypnotics (thiamylal), local anesthetics (lidocaine), depolarizing muscular relaxants (vecuronium), an antihypertensive (clonidine) and an H2-receptor antagonist (cimetidine) using human liver microsomes in vitro. METHODS: The interaction effects between propofol and premedications were examined using human liver microsomal preparation in vitro. The concentration of propofol was determined by HPLC with UV detection. RESULTS: The apparent Michaelis-Menten constant (Km) and the maximal velocity of total metabolic formation (Vmax) of propofol in human liver microsomes were 123 microM and 26.1 micromol/min per milligram of mg protein, respectively. Seven premedications (diazepam, midazolam, thiamylal, lidocaine, cimetidine, vecuronium, and clonidine) did not inhibit propofol metabolism in human liver microsomes at concentrations within the therapeutic range. CONCLUSIONS: These results showed no interactions between propofol and seven premedication drugs within the therapeutic range of propofol using human liver microsomes in vitro.