The pharmacokinetics of propofol in laboratory animals

Cockshott, I. D.; Douglas, Elaine; Plummer, Greg; Simons, Peter J.

doi:10.3109/00498259209046648

Cited by 148 publications

(90 citation statements)

References 16 publications

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“…The pharmacokinetics of propofol are generally described by two-or three-com- partment models in which blood levels after a single bolus fall according to two or three exponentials. The half-time of the first exponential component, representing extensive redistribution from a large central compartment into a volume much greater than total body volume, is 3.5 min in rats (Cockshott et al, 1992) and in the range of 1.6 to 4.2 min in humans (Saint-Maurice et al, 1989). This initial redistribution probably accounts for the rapid recovery seen in the present study.…”

Section: Discussionsupporting

confidence: 52%

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Dhir

Żółkowska

Murphy³

et al. 2010

J Pharmacol Exp Ther

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The lung provides a portal of entry for drug delivery that could be used to administer anticonvulsant substances to prevent or abort seizures. Here, we demonstrate that intrapulmonary propofol hemisuccinate (PHS) rapidly confers seizure protection in various rodent chemoconvulsant models. Propofol is a powerful anticonvulsant substance at subanesthetic doses, but it is a viscous, water-immiscible oil that is not suitable for intrapulmonary administration. We found that PHS can be formulated as an aqueous solution that is well tolerated when instilled into the lung. High-dose intraperitoneally administered PHS induced loss-of-righting reflex in rats and mice. The onset of action of PHS was delayed in comparison with propofol, suggesting that conversion to propofol is required for activity. A lower dose of PHS (40 mg/kg i.p.) did not cause general anesthesia but protected against pentylenetetrazol (PTZ)-induced seizures in rats. Intrapulmonary administration of an aqueous PHS solution via a tracheal cannula at lower doses (5 and 10 mg/kg) conferred equivalent seizure protection without acute motor toxicity. In mice, intraperitoneal PHS (60 -80 mg/kg) was associated with an elevation in PTZ, bicuculline, picrotoxin, and kainic acid seizure thresholds. Intratracheal PHS was markedly more potent, producing seizure threshold elevations at doses of 10 to 15 mg/kg. In the PTZ threshold model in mice, PHS was active at 5 min, maximally active at 10 min, and no longer active at 20 min. Intratracheal PHS also prolonged the onset of 4-aminopyridine-induced convulsions but did not affect the threshold for N-methyl-D-aspartate-induced convulsions. We conclude that intratracheal administration of an aqueous solution of PHS, a putative propofol prodrug, provides potent seizure protection of rapid onset and brief duration. Intrapulmonary PHS may be useful for preventing the spread of seizures or aborting seizure clusters without causing prolonged sedation.

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Section: Discussionsupporting

confidence: 52%

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Dhir

Żółkowska

Murphy³

et al. 2010

J Pharmacol Exp Ther

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“…In this species, recovery times may be prolonged after continuous infusion of propofol for more than 30 min (Robertson et al 1992). It can be assumed that the same effect could occur in rabbits, as propofol pharmacokinetics are similar in these two species (Cockshott et al 1992). Reports in humans state that recovery times are not prolonged after long-duration sevoflurane anaesthesia (Ebert et al 1998), although this is not entirely clear, as other data indicate that recovery times after sevoflurane anaesthesia increase with the duration of anaesthesia (Eger et al 1998).…”

Section: Resultsmentioning

confidence: 65%

Relationship of bispectral index values, haemodynamic changes and recovery times during sevoflurane or propofol anaesthesia in rabbits

et al. 2006

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SummaryThe aim of this study was to determine and compare the degree of hypnosis achieved during propofol or sevoflurane anaesthesia in rabbits using bispectral index (BIS), and to evaluate its usefulness as a predictor of both haemodynamic changes during anaesthesia and recovery times. Twenty adult male New Zealand White rabbits, average weight 4.470.4 kg, were used for this study. Animals were randomly allocated to one of two groups with 10 rabbits/group. An electroencephalographic recording was obtained from each conscious rabbit prior to drug administration. All animals received buprenorphine as a preanaesthetic medication (0.05 mg/kg, intravenous [i.v.]). Anaesthesia was induced with propofol (8 mg/kg, i.v.) in all animals; 10 rabbits were maintained with sevoflurane via inhalation (1 minimum alveolar concentration -end-tidal sevoflurane concentration of 3.7% -at a fresh gas flow rate of 3 L/ min; group I), and 10 were maintained with i.v. propofol (0.6 mg/kg/min; group II). The rabbits were orotracheally intubated and spontaneous ventilation was maintained throughout the study (100% oxygen). After abdominal surgery through a ventral midline laparotomy, rabbits were allowed to recover from anaesthesia. Cardiovascular variables and BIS values were recorded at intervals throughout the procedure, as was the duration of recovery from anaesthesia.In both groups, mean BIS values were significantly decreased immediately after induction, compared with baseline values obtained during consciousness. Anaesthetic depth (evaluated by clinical observation) was similar in both groups; however, group II rabbits had significantly higher (Po0.001) BIS values from 30 s before incision until anaesthesia was discontinued. There was no significant difference in BIS recorded 1 and 5 min after incision as compared with values obtained 30 s before incision in either group.During sevoflurane or propofol administration, correlations were found between BIS values and mean arterial blood pressure (MABP), and between BIS values and heart rate (HR).Mean BIS values at discontinuation of administration of the anaesthetic agent were greater in group II (69.176.0) than in group I (49.372.2). However, recovery from anaesthesia was significantly longer in group II (38.477.2 min) than in group I (11.572.5 min).In conclusion, BIS can be used to differentiate between conscious and unconscious states during anaesthesia in rabbits. BIS values derived from an electroencephalogram at the end of anaesthesia were not useful for predicting the speed of anaesthetic recovery in sevoflurane or propofol-anaesthetized rabbits undergoing abdominal surgery. Despite the correlation found Correspondence: Marı´a Fernanda Martı´n Cancho, Minimally

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“…Our data suggest that propofol binds to a site(s) on the Na+ channel that is exposed or formed in the inactivated conformation of the channel. Further experiments will be required to determine whether this site (s) (Cockshott et al, 1992), the inhibitory effects of propofol on Na+ channels should occur at much lower free concentrations.…”

Section: Discussionmentioning

confidence: 99%

Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

Lingamaneni

Hemmings

1996

British J Pharmacology

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The pharmacokinetics of propofol in laboratory animals

Cited by 148 publications

References 16 publications

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Relationship of bispectral index values, haemodynamic changes and recovery times during sevoflurane or propofol anaesthesia in rabbits

Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

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The pharmacokinetics of propofol in laboratory animals

Cited by 148 publications

References 16 publications

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Relationship of bispectral index values, haemodynamic changes and recovery times during sevoflurane or propofol anaesthesia in rabbits

Inhibition by propofol of [3H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes

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Inhibition by propofol of [³H]‐batrachotoxinin‐A 20‐α‐benzoate binding to voltage‐dependent sodium channels in rat cortical synaptosomes