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Titolo:
In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep
Autore:
Upton, RN; Ludbrook, GL; Grant, C; Martinez, A;
Indirizzi:
Univ Adelaide, Royal Adelaide Hosp, Dept Anaesthesia & Intens Care, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 re, Adelaide, SA 5005, Australia
Titolo Testata:
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
fascicolo: 2, volume: 28, anno: 2001,
pagine: 129 - 153
SICI:
1567-567X(200104)28:2<129:IVCPAP>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOPPLER VENOUS OUTFLOW; BLOOD-FLOW; P-GLYCOPROTEIN; CEREBROSPINAL-FLUID; HEALTHY-VOLUNTEERS; RECEPTOR-BINDING; PROTEIN-BINDING; BRAIN UPTAKE; IN-VIVO; MODEL;
Keywords:
midazolam; diazepam; cerebral blood flow; cerebral pharmacokinetics; lung pharmacokinetics; pharmacodynamics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Upton, RN Univ Adelaide, Royal Adelaide Hosp, Dept Anaesthesia & Intens Care, North Terrace, Adelaide, SA 5005, Australia Univ Adelaide North TerraceAdelaide SA Australia 5005 Australia
Citazione:
R.N. Upton et al., "In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep", J PHARMA PH, 28(2), 2001, pp. 129-153

Abstract

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their after io-venous concentration difference across the brain during and after 2-min iv infusions. Diazepam (30 mg) or min'azolam (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. lit a subset of sheep, pulmonary arterial-arterial gradientswere too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurementsof cerebral bloodflow 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 bloodflow data showed apparent effect compartment half-lives (t(1/2,keo)) that were longer than the half-lives of cerebralequilibration.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 01:47:21