Pharmacokinetics and pharmacodynamics of eltanolone (pregnanolone), a new steroid intravenous anaesthetic, in humans.
Eltanolone, a new intravenous steroid anaesthetic agent was administered intravenously in a dose of 0.6 mg.kg-1 over 45 s to eight healthy male volunteers to evaluate some of its pharmacokinetic and pharmacodynamic effects. Drug concentration-time data were analysed by PCNONLIN, a non-linear regression programme, showing data consistent with a three-compartment model with initial distribution half-life t1/2 lambda 1 between 0.3 and 2 min, intermediate distribution half-life t1/2 lambda 2 between 12 and 29 min and terminal half-life t1/2 lambda z between 72 and 212 min. The total body clearance of eltanolone was rapid and with individual values in the range 1.6-2.3 l.h-1.kg-1. Eltanolone was initially distributed into a relatively large central compartment V1 between 0.09 and 0.98 l.kg-1 and then extensively further distributed (Vss between 1.80 and 5.44 l.kg-1 and V between 4.87 and 11.87 l.kg-1). The excretion of unchanged of eltanolone in urine was very small, the renal clearance was less than 0.5% of the total clearance. Induction of anaesthesia was trouble free with onset and duration of anaesthesia between 1-2 min and 6-13 min, respectively. There was slight respiratory depression, a small transient increase in heart rate, and a maximum reduction in arterial blood pressure of 23%, as compared with the resting level. Pain on injection and venous sequelae were not seen. Involuntary movements were seen in one subject. We conclude that eltanolone has a favourable pharmacokinetic profile with relatively rapid half-lives, large distribution volumes and rapid total body clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
Carl
P
P
Department of Anaesthesiology and Intensive Care, Hvidovre University Hospital, Denmark.
Høgskilde
S
S
Lang-Jensen
T
T
Bach
V
V
Jacobsen
J
J
Sørensen
M B
MB
Grälls
M
M
Widlund
L
L
D000328:Adult; D018686:Anesthetics, Intravenous / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001767:Blinking / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011280:Pregnanolone / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D011280:Pregnanolone