Pharmacokinetics of eltanolone following bolus injection and constant rate infusion |
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Authors: | Kourosh Parivar Arne Wessén Marianne Widman Anders Nilsson |
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Institution: | (1) Department of Clinical Pharmacology, Hospital Care, R&D, Pharmacia AB, S-112 87 Stockholm, Sweden;(2) Department of Anaesthesiology, University Hospital, S-751 85 Uppsala, Sweden |
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Abstract: | Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and
constant rate intravenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous
blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone
concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis,
the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic
parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80
(0.23–5.47) min (B), 1.44 (0.97–2.06) min (I2) and 1.44 (0.95–2.39) min (I3.5), an intermediate phase with a half-life of
35.4 (28.7–45.2) min (B), 39.6 (31.0–47.9) min (I2) and 35.4 (33.3–44.9) min (I3.5) and a moderately short terminal phase
with a half-life of 3.8 (2.7–5.9) hr (B), 5.0 (4.2–6.1) hr (I2) and 4.6 (4.0–4.8) hr (I3.5). The serum clearance after bolus
injection was 1.37 (1.23–1.67) L/hr/kg and after infusion was 1.36 (1.25–1.52) L/hr/kg (I2) and 1.17 (1.11–1.31) L/hr/kg (I3.5).
The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained
after bolus injection were very much similar to the parameters obtained after infusion with the exception of t1/2β which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not
significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after
different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration,
is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion
of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value
of 70–80 min following an infusion of 10 hr. |
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Keywords: | eltanolone pregnanolone Kabi 2213 context sensitive time anaesthesia healthy volunteers pharmacokinetics |
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