Brain and Blood Concentrations of Propofol after Rapid Intravenous Injection in Sheep, and Their Relationships to Cerebral Effects

Ludbrook, Guy L.; Upton, Richard N.; Grant, Cliff; Gray, Elke C.

doi:10.1177/0310057x9602400406

Cited by 47 publications

(25 citation statements)

References 24 publications

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“…In addition, a hysteresis exists between arterial propofol concentration and anesthetic effect, whereas brain propofol has a close relationship with cerebral blood flow and depth of anesthesia in a sheep model of propofol pharmacokinetics (Ludbrook et al, 1996). In the rat, brain propofol concentrations correlate with tail-flick latency after propofol administration (Shyr et al, 1995), which indicates that the local concentration of propofol in the brain contributes to the drug's effect.…”

Section: Introductionmentioning

confidence: 99%

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Khokhar

Tyndale

2010

Neuropsychopharmacol

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Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.

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Section: Introductionmentioning

confidence: 99%

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Khokhar

Tyndale

2010

Neuropsychopharmacol

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“…1,2 Chronic instrumentation of animals with a sagittal sinus Doppler probe allows multiple studies over several weeks in awake or anaesthetized animals. This direct Doppler method can characterize the rapid changes in CBF induced by some drugs and has been carefully validated against volumetric sagittal sinus blood outflow over a wide range of flows.…”

Section: Introductionmentioning

confidence: 99%

Agreement Between Ultrasonic Doppler Venous Outflow and Kety and Schmidt Estimates Of Cerebral Blood Flow

Doolette

Rn²,

Grant³

1999

Clin Exp Pharmacol Physiol

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1. The present study compares the indirect Fick nitrous oxide equilibration method of Kety and Schmidt for cerebral blood flow (CBF) estimation with a direct ultrasonic Doppler index of venous outflow. 2. Cerebral blood flow was determined simultaneously by the direct measurement of sagittal sinus blood velocity and the indirect Kety and Schmidt method in five anaesthetized sheep during high and low steady states of CBF. High- and low-flow states were achieved by altering ventilation to produce hypercarbia and hypocarbia, respectively. 3. Four different sets of calculations were used to make the Kety and Schmidt estimations: arterial-venous nitrous oxide concentration differences during uptake or elution of the indicator and with or without extrapolation of arterial-venous differences to infinity. 4. During 15 min nitrous oxide administration, apparent blood:tissue equilibration of nitrous oxide was rapid in some data sets and slow in others. 5. There were no significant differences in CBF estimates between any of the four Kety and Schmidt calculations or the direct ultrasonic Doppler venous outflow method; however, CBF estimates based on nitrous oxide uptake correlated more strongly with the direct method than estimates based on nitrous oxide elution. 6. In the high-flow state, CBF estimates based on nitrous oxide uptake, but not those based on elution, distinguished between rapid and slow blood:tissue equilibration of nitrous oxide. 7. This provides validation of the Doppler sheep brain venous outflow method against the widely used Kety and Schmidt method.

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“…In most cases, only the unbound fraction is able to interact with Na + channels. Therefore, a higher concentration was used in pain therapy [55]. Propofol is mainly eliminated by hepatic conjugation to inactive metabolites, which are secreted from the kidney [56].…”

Section: Discussionmentioning

confidence: 99%

Chitosan Oligosaccharide Reduces Propofol Requirements and Propofol-Related Side Effects

Yang

Song

et al. 2016

Marine Drugs

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Propofol is one of the main sedatives but its negative side effects limit its clinical application. Chitosan oligosaccharide (COS), a kind of natural product with anti-pain and anti-inflammatory activities, may be a potential adjuvant to propofol use. A total of 94 patients receiving surgeries were evenly and randomly assigned to two groups: 10 mg/kg COS oral administration and/or placebo oral administration before being injected with propofol. The target-controlled infusion of propofol was adjusted to maintain the values of the bispectral index at 50. All patients’ pain was evaluated on a four-point scale and side effects were investigated. To explore the molecular mechanism for the functions of COS in propofol use, a mouse pain model was established. The activities of Nav1.7 were analyzed in dorsal root ganglia (DRG) cells. The results showed that the patients receiving COS pretreatment were likely to require less propofol than the patients pretreated with placebo for maintaining an anesthetic situation (p < 0.05). The degrees of injection pain were lower in a COS-pretreated group than in a propofol-pretreated group. The side effects were also more reduced in a COS-treated group than in a placebo-pretreated group. COS reduced the activity of Nav1.7 and its inhibitory function was lost when Nav1.7 was silenced (p > 0.05). COS improved propofol performance by affecting Nav1.7 activity. Thus, COS is a potential adjuvant to propofol use in surgical anesthesia.

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Brain and Blood Concentrations of Propofol after Rapid Intravenous Injection in Sheep, and Their Relationships to Cerebral Effects

Cited by 47 publications

References 24 publications

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Agreement Between Ultrasonic Doppler Venous Outflow and Kety and Schmidt Estimates Of Cerebral Blood Flow

Chitosan Oligosaccharide Reduces Propofol Requirements and Propofol-Related Side Effects

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