Pharmacokinetics and pharmacodynamics of eltanolone (pregnanolone), a new steroid intravenous anaesthetic, in humans

Abstract

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)

Pharmacokinetic and behavioral effects of allopregnanolone in healthy women

“…It should be noted that allopregnanolone is rapidly metabolized to 5α-pregnane-3,20-dione, which is a potent progestin (Milewich et al 1979), which in turn could explain the endometrial shedding. Pregnanolone, the 5β-epimer of allopregnanolone, which is not metabolized to an active progestin, has previously been investigated in humans, predominantly for the induction of anesthesia (Carl et al 1990(Carl et al , 1994. The sedative effects of pregnanolone have been studied across different hormonal conditions, such as the menstrual cycle and during hormone replacement therapy Wihlback et al 2001Wihlback et al , 2005, and depend on endogenous concentrations of neuroactive steroids.…”

Relationships of circulating pregnanolone isomers and their polar conjugates to the status of sex, menstrual cycle, and pregnancy

“…At lower concentrations, P3a5a paradoxically acts as neurostimulant showing a neuroinhibiting effect as late as at levels comparable with the concentrations common in pregnancy . Moreover, one of the neuroinhibiting PIs, P3a5b is an unstable substance with a short half-life in the human organism (Carl et al 1994). P3a5b is identical to a short-term central anesthetic eltanolone that has previously been tested in pharmacological studies (Hering et al 1996).…”

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

“…The solvent might be of importance for the half-life by creating a possible depot from which the substance is slowly released, as shown for pregnanolone (Carl et al 1994;Sundstrom et al 1999b). However, both allopregnanolone and isoallopregnanolone were administrated in a similar albumin solution.…”