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dc.contributor.authorUpton, R.en
dc.contributor.authorLudbrook, G.en
dc.contributor.authorGrant, C.en
dc.contributor.authorMartinez, A.en
dc.identifier.citationJournal of Pharmacokinetics and Pharmacodynamics, 2001; 28(2):129-153en
dc.description.abstractThe cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their arterio-venous concentration difference across the brain during and after 2-min iv infusions. Diazepam (30 mg) or midazolam (10 mg) were administered on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral uptake occurred during the infusion, which quickly turned to elution in the postinfusion period. However, this process was more rapid for midazolam than diazepam. The cerebral pharmacokinetics of both was better described by a kinetic model with slight membrane limitation rather than flow limitation. For diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 min, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. In a subset of sheep, pulmonary arterial–arterial gradients were too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral blood flow and algesimetry lagged behind both the arterial and sagittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13.3 and 5.5 min for midazolam and diazepam, respectively). Effect compartment modeling of the cerebral blood flow data showed apparent effect compartment half-lives (t_1/2,keo) that were longer than the half-lives of cerebral equilibration.en
dc.description.statementofresponsibilityUpton R.N., Ludbrook G.L., Grant C. and Martinez A.en
dc.publisherKluwer Academic/Plenum Publen
dc.subjectmidazolam; diazepam; cerebral blood flow; cerebral pharmacokinetics; lung pharmacokinetics; pharmacodynamicsen
dc.titleIn vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheepen
dc.typeJournal articleen
pubs.library.collectionAnaesthesia and Intensive Care publicationsen
dc.identifier.orcidUpton, R. [0000-0001-9996-4886]en
dc.identifier.orcidLudbrook, G. [0000-0001-6925-4277]en
Appears in Collections:Anaesthesia and Intensive Care publications

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