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Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: an application of mass balance pharmacokinetics with a changing regional blood flow

Björkman, Sven; Åkeson, Jonas LU ; Nilsson, Fritiof; Messeter, Kenneth and Roth, Bodil (1992) In Journal of Pharmacokinetics and Biopharmaceutics 20(6). p.637-652
Abstract
Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF) by one third, as measured by intermittent 133Xe washout. By means of pharmacodynamic models, the effects on the CBF could be predicted from the arterial drug concentrations. The high-resolution CBF vs. time curves thus generated allowed the calculation of cerebral drug levels from arterio-venous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF, ketamine and midazolam decrease... (More)
Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF) by one third, as measured by intermittent 133Xe washout. By means of pharmacodynamic models, the effects on the CBF could be predicted from the arterial drug concentrations. The high-resolution CBF vs. time curves thus generated allowed the calculation of cerebral drug levels from arterio-venous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF, ketamine and midazolam decrease their own rate of transport to the brain, the immediate 30-35% drops in CBF giving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBF is determined mainly by the effects of the anesthetics and by the arterial CO2 tension. CBF changes in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ketamine, midazolam, mass balance, brain, cerebral blood flow
in
Journal of Pharmacokinetics and Biopharmaceutics
volume
20
issue
6
pages
637 - 652
publisher
Springer
external identifiers
  • pmid:1302766
  • scopus:0027075205
ISSN
0090-466X
DOI
10.1007/BF01064423
language
English
LU publication?
yes
id
430921bd-04b4-4c44-8c9f-2b3b53109380 (old id 1106636)
date added to LUP
2008-07-31 10:34:11
date last changed
2017-01-01 07:20:04
@article{430921bd-04b4-4c44-8c9f-2b3b53109380,
  abstract     = {Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF) by one third, as measured by intermittent 133Xe washout. By means of pharmacodynamic models, the effects on the CBF could be predicted from the arterial drug concentrations. The high-resolution CBF vs. time curves thus generated allowed the calculation of cerebral drug levels from arterio-venous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF, ketamine and midazolam decrease their own rate of transport to the brain, the immediate 30-35% drops in CBF giving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBF is determined mainly by the effects of the anesthetics and by the arterial CO2 tension. CBF changes in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.},
  author       = {Björkman, Sven and Åkeson, Jonas and Nilsson, Fritiof and Messeter, Kenneth and Roth, Bodil},
  issn         = {0090-466X},
  keyword      = {ketamine,midazolam,mass balance,brain,cerebral blood flow},
  language     = {eng},
  number       = {6},
  pages        = {637--652},
  publisher    = {Springer},
  series       = {Journal of Pharmacokinetics and Biopharmaceutics},
  title        = {Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: an application of mass balance pharmacokinetics with a changing regional blood flow},
  url          = {http://dx.doi.org/10.1007/BF01064423},
  volume       = {20},
  year         = {1992},
}