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Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

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Abstract

Rationale

The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known.

Objectives

Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well-known neurosteroid, acting via the GABAA receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABAA receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABAA receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.

Materials and methods

Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.

Results

Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.

Conclusions

After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.

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Acknowledgements

This study was supported by grants from the Swedish Research Council, medicine proj. 4X-11198, EU structural fund objective 1 program, Umeå University foundations, Västerbottens läns landsting, Umeå kommun. The study complies with Swedish law regarding ethical considerations in human experiments.

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Authors and Affiliations

  1. Umeå Neurosteroid Research Center, Department of Clinical Science, Obstetrics, and Gynecology, Umeå University, Umeå, Sweden

    Helena Hedström, Marie Bixo, Sigrid Nyberg, Elisabeth Zingmark & Torbjörn Bäckström

  2. Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway

    Olav Spigset

  3. Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway

    Olav Spigset

  4. Umeå Neurosteroid Research Center, Norrlands University Hospital, Building 5B, 5th Floor, 901 85, Umeå, Sweden

    Torbjörn Bäckström

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  1. Helena Hedström
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Correspondence to Torbjörn Bäckström.

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Hedström, H., Bixo, M., Nyberg, S. et al. Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women. Psychopharmacology 203, 85–98 (2009). https://doi.org/10.1007/s00213-008-1372-8

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