Steroid anesthetics: Old compounds, new drugs

Sear, J.W.

doi:10.1016/s0952-8180(96)90021-5

Cited by 35 publications

(40 citation statements)

References 52 publications

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“…The various neuroactive steroids exhibit similar pharmacokinetic characteristics, such as a very short distribution halflife and an elimination half-life between 20 and 50 min. The value of the clearance is around ϳ20 ml ⅐ min Ϫ1 , which is equal to the rat liver blood flow, suggesting hepatic elimination with a high extraction ratio (Sear, 1996;Visser et al, 2000Visser et al, , 2002. The volume of distribution at steady state is larger for pregnanolone (ϳ1.8 l ⅐ kg Ϫ1 ) than for alphaxalone and ORG 21465 (ϳ0.8 l ⅐ kg Ϫ1 ).…”

Section: Discussionmentioning

confidence: 95%

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Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Visser¹,

Gladdines²,

Graaf³

et al. 2002

J Pharmacol Exp Ther

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The objective of the present investigation was to characterize the in vivo EEG effects of (synthetic) neuroactive steroids on the basis of a recently proposed mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model. After intravenous administration, the time course of the EEG effect of pregnanolone, 2␤-3␣-5␣-3-hydroxy-2-(2,2-dimethylmorpholin-4-yl)-pregnan-11,20-dione (ORG 21465), 2␤-3␣-5␣-21-chloro-3-hydroxy-2-(4-morpholinyl)-pregnan-20-one (ORG 20599), and alphaxalone was determined in conjunction with plasma concentrations in rats. For each neuroactive steroid the PK/PD correlation was described on the basis of a two-compartment pharmacokinetic model with an effect compartment to account for hysteresis. The observed concentration EEG effect relationships were biphasic and characterized with a mechanism-based pharmacodynamic model, which is based on a separation between the receptor activation process and the stimulus-response relationship. A single unique biphasic stimulus-response relationship could be identified for all neuroactive steroids, which was successfully described by a parabolic function. The receptor activation process was described by a hyperbolic function. Estimates for the maximum activation (e PD ) were similar for the different neuroactive steroids but values of the potency estimate (K PD ) ranged from 157 Ϯ 16 ng ⅐ ml Ϫ1 for pregnanolone, 221 Ϯ 83 ng ⅐ ml Ϫ1 for ORG 20599, and 483 Ϯ 42 ng ⅐ ml Ϫ1 for alphaxalone to 1619 Ϯ 208 ng ⅐ ml Ϫ1 for ORG 21465. A statistically significant correlation was observed between the in vivo potency and the IC 50 in an in vitro [ 35 S]t-butylbicyclophosphorothionate binding assay (r ϭ 0.91). It is concluded that the new PK/PD model constitutes a new mechanism-based approach to the quantification of the effects of (synthetic) neuroactive steroids in vivo effects. The results show that the neuroactive steroids differ in potency but not in intrinsic efficacy at the GABA A receptor in vivo.

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Section: Discussionmentioning

confidence: 95%

“…Interestingly, the pharmacokinetics in rats shows great similarity to that in humans. In humans, a clearance of ϳ25 ml min Ϫ1 kg Ϫ1 and a volume of distribution at steady state between 0.7 and 2.5 l ⅐ kg Ϫ1 have been reported for pregnanolone, alphaxalone, and ORG 21465 (Hering et al, 1996;Sear, 1996;Sneyd et al, 1997a,b).…”

Section: Discussionmentioning

confidence: 99%

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Visser¹,

Gladdines²,

Graaf³

et al. 2002

J Pharmacol Exp Ther

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“…It has been shown that alphaxalone is rapidly metabolized to inactive metabolites by the hepatic mixed function oxygenase system (Sear and McGivan, 1981). A fast hepatic clearance and low oral bioavailability was also reported for humans (Sear, 1996). The volume of distribution (V 2 ) for the lowest dose (group A) was significantly lower than for the other groups.…”

Section: Discussionmentioning

confidence: 96%

“…This initial work led to the introduction of the synthetic neuroactive steroid alphaxalone (5␣-pregnan-3␣-ol-11,20-dione) into clinical medicine (Sear, 1996). Alphaxalone exerts its selective action via a specific binding site at the GABA A receptor complex and does not interact with any of the classical cytosolic hormonal steroid receptors (Paul and Purdy, 1992;Lambert et al, 1995).…”

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Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Visser

Smulders²,

Reijers³

et al. 2002

J Pharmacol Exp Ther

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The neuroactive steroid alphaxalone reveals a complex biphasic concentration-effect relationship using the 11.5 to 30 Hz frequency band of the electroencephalogram (EEG) as biomarker. The purpose of the present investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic model to describe this observation. The proposed model is based on receptor theory and aims to separate the drug-receptor interaction from the transduction of the initial stimulus into the observed biphasic response. Individual concentration-time courses of alphaxalone were obtained in combination with continuous recording of the EEG parameter. Alphaxalone was administered intravenously in various dosages. The pharmacokinetics were described by a two-compartment model, and parameter estimates for clearance, intercompartmental clearance, volume of distribution 1 and 2 were 158 Ϯ 29 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 , 143 Ϯ 31 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 , 122 Ϯ 20 ml ⅐ kg Ϫ1 and 606 Ϯ 48 ml ⅐ kg Ϫ1 , respectively. Concentration-effect relationships exhibited a biphasic pattern and delay in onset of effect. The hysteresis was described on the basis of an effect-compartment model with C max as covariate. The pharmacodynamic model consisted of a receptor model, featuring a monophasic saturable receptor activation model in combination with a biphasic stimulus-response model. The in vivo affinity (K PD ) was estimated at 432 Ϯ 26 ng ⅐ ml Ϫ1 . Unique parameter estimates were obtained that were independent of the dose and the duration of the infusion. In conclusion, we have shown that this mechanism-based approach, which separates drug-and system-related properties in vivo, was successfully applied for the characterization of the biphasic effect versus time patterns of alphaxalone. The model should be of use in the characterization of other biphasic responses.The sedative-hypnotic and anesthetic properties of a wide range of natural and synthetic steroids were first shown by Selye (1942). This initial work led to the introduction of the synthetic neuroactive steroid alphaxalone (5␣-pregnan-3␣-ol-11,20-dione) into clinical medicine (Sear, 1996). Alphaxalone exerts its selective action via a specific binding site at the GABA A receptor complex and does not interact with any of the classical cytosolic hormonal steroid receptors (Paul and Purdy, 1992;Lambert et al., 1995). Detailed mechanistic investigations have revealed a dual mechanism of action for alphaxalone. Low concentrations of alphaxalone allosterically modulate the amplitude of GABA-induced ion currents, whereas alphaxalone at higher concentrations (Ն1 M) acts as an agonist, similar to that observed by barbiturates (Cottrell et al., 1987;Paul and Purdy, 1992;Lambert et al., 1995). Recently, there has been a renewed interest in neuroactive steroids in relation to the development of novel strategies for the treatment of anxiety, insomnia, migraine, depression, and seizure disorders (Gasior et al., 1999). However, very few attempts have been made to study neuroactive steroids in vivo on the basi...

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Pharmacology in Veterinary Anesthesia and Analgesia

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Steroid anesthetics: Old compounds, new drugs

Cited by 35 publications

References 52 publications

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

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Steroid anesthetics: Old compounds, new drugs

Cited by 35 publications

References 52 publications

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABAAReceptor in Vivo

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABAAReceptor in Vivo

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of Concentration-Dependent Hysteresis and Biphasic Electroencephalogram Effects of Alphaxalone in Rats

Induction Drugs

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Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo

Neuroactive Steroids Differ in Potency but Not in Intrinsic Efficacy at the GABA_AReceptor in Vivo