Preparation, Characterization, and Anesthetic Properties of 2-Hydroxypropyl-β-cyclodextrin Complexes of Pregnanolone and Pregnenolone in Rat and Mouse

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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“…This was also reported for the bioavailability and onset of effect of pregnanolone and pregnenolone (Brewster et al, 1995).…”

supporting

confidence: 65%

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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“…Progesterone was purchased already encapsulated in HBC, and concentrations were based on the amount of progesterone, not the amount of HBC-progesterone, in solution. HBC enhances the water solubility of progesterone, and does not detrimentally affect the pharmacokinetic properties of steroid hormones (Brewster et al, 1995). Because this form of progesterone is metabolized within hours (Pitha et al, 1986), it is likely not in circulation during either phase of behavioral testing, thus, minimizing confounding effect of non-mnemonic performance factors (e.g., motivation, anxiety) on performance.…”

Section: Methodsmentioning

confidence: 99%

Dorsal hippocampal progesterone infusions enhance object recognition in young female mice

Orr

Lewis

Frick

2009

Pharmacology Biochemistry and Behavior

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The effects of progesterone on memory are not nearly as well studied as the effects of estrogens. Although progesterone can reportedly enhance spatial and/or object recognition in female rodents when given immediately after training, previous studies have injected progesterone systemically, and therefore, the brain regions mediating this enhancement are not clear. As such, this study was designed to determine the role of the dorsal hippocampus in mediating the beneficial effect of progesterone on object recognition. Young ovariectomized C57BL/6 mice were trained in a hippocampal-dependent object recognition task utilizing two identical objects, and then immediately or 2 hrs afterwards, received bilateral dorsal hippocampal infusions of vehicle or 0.01, 0.1, or 1.0 μg/μl water-soluble progesterone. Forty-eight hours later, object recognition memory was tested using a previously explored object and a novel object. Relative to the vehicle group, memory for the familiar object was enhanced in all groups receiving immediate infusions of progesterone. Progesterone infusion delayed 2 hrs after training did not affect object recognition. These data suggest that the dorsal hippocampus may play a critical role in progesterone-induced enhancement of object recognition.

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“…More recently, the same research group provided additional data showing the usefulness of HP--CD in the parenteral administration of a series of other steroidal anesthetic agents. 68 Doenicke et al 69 compared the iv bolus pharmacokinetics and activity of the hypnotic agent etomidate (2 mg‚mL -1 ) from a 35% propylene glycol aqueous solution compared to a 3% HP--CD solution. The pharmacokinetics of etomidate were identical from the two solutions, and no differences in hypnotic effects were observed.…”

Section: Parenteral Applications Of Cyclodextrinsmentioning

confidence: 99%

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

Rajewski¹,

Stella²

1996

Journal of Pharmaceutical Sciences

759

374

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The objective of this Review is to summarize and critique recent findings and applications of both unmodified and modified cyclodextrins for in vivo drug delivery. This review focuses on the use of cyclodextrins for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal, rectal, and pulmonary delivery are also briefly addressed. This Review primarily focuses on newer findings concerning cyclodextrin derivatives which are likely to receive regulatory acceptance due to improved aqueous solubility and safety profiles as compared to the unmodified cyclodextrins. Many of the applications reviewed involve the use of hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) and sulfobutylether-beta-cyclodextrins (SBE-beta-CDs) which show promise of greater safety while maintaining the ability to form inclusion complexes. The advantages and limitations of HP-beta-CD, SBE-beta-CD, and other cyclodextrins are addressed.

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Preparation, Characterization, and Anesthetic Properties of 2-Hydroxypropyl-β-cyclodextrin Complexes of Pregnanolone and Pregnenolone in Rat and Mouse

Cited by 26 publications

References 41 publications

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

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

Dorsal hippocampal progesterone infusions enhance object recognition in young female mice

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

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