Title

Female Sex Hormones Alter GHB Toxicokinetics

Poster Number

3B

Lead Author Affiliation

Biopharmaceutical Sciences

Lead Author Status

Doctoral Student

Second Author Affiliation

Pharmaceutics and Medicinal Chemistry

Second Author Status

Staff

Third Author Affiliation

Biopharmaceutical Sciences

Third Author Status

Doctoral Student

Fourth Author Affiliation

Pharmaceutics and Medicinal Chemistry

Fourth Author Status

Faculty

Introduction

Gamma-Hydroxybutyrate (GHB) is an endogenous short-chain fatty acid formed from gamma-aminobutyric acid (GABA). Clinically, GHB is marketed in the United States as Xyrem to treat narcolepsy with cataplexy and in Europe for the treatment of alcohol withdrawal and narcolepsy. However, the illicit use and abuse of GHB occurs due to its sedative/hypnotic and euphoric effects. Sex differences in drug elimination pathways contribute to inter-individual variability observed between sexes with respect to drug disposition and effect. Our previous results demonstrated that GHB toxicokinetics varies over the estrus cycle, and between males and females; however, there is an absence of information on how the individual female sex hormones influence GHB toxicokinetics.

Purpose

To evaluate the influence of estrogen and progesterone on GHB toxicokinetics following sex and cross-sex hormone administration.

Method

GHB toxicokinetics and renal clearance were evaluated in male, female, ovariectomized (OVX) females and castrated (CST) male Sprague-Dawley rats treated. OVX or CST surgery was performed at 8 weeks of age. At 10 weeks of age, OVX females and CST males were treated with 60-day release pellets of 17β-estradiol (1.5 mg) and/or progesterone (50 mg) or corresponding placebos for 21 days (N = 5 – 6 per group). GHB (1000 mg/kg) was administered by intravenous bolus injection via a jugular vein cannula to all groups of rats. GHB concentration in the plasma and urine was quantified using LCMS. Non-compartmental analysis of the plasma-concentration time profiles was conducted in Phoenix WinNonLin.

Results

Our results indicate that female sex hormones alter GHB toxicokinetics. OVX estrogen, OVX progesterone, OVX combo and female (estrus) groups have significantly lower AUCs and total clearance than males. In CST combo rats, AUC trended lower than intact males. Significantly higher total clearance was observed in OVX combo and female groups compared with males (P=0.007). CST combo had significantly higher total clearance than male (P=0.0415). Combo-treated OVX/CST and female (estrus) rats have significantly higher metabolic clearance than male and placebo-treated rats (POVX<0.0001 and PCST<0.0001).

Significance

The focus of this study is on investigating GHB toxicokinetics in response to sex and cross-sex hormone therapy and help to identify populations with a greater risk of GHB overdose. The animal model of cross-sex hormone treatment in the current proposal is consistent with individuals that have undergone gender confirmation surgery and could be used to evaluate the toxicokinetics of other drugs of abuse.

Location

William Knox Holt Memorial Library and Learning Center, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211

Format

Poster Presentation

Poster Session

Morning

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Apr 30th, 10:00 AM Apr 30th, 12:00 PM

Female Sex Hormones Alter GHB Toxicokinetics

William Knox Holt Memorial Library and Learning Center, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211

Gamma-Hydroxybutyrate (GHB) is an endogenous short-chain fatty acid formed from gamma-aminobutyric acid (GABA). Clinically, GHB is marketed in the United States as Xyrem to treat narcolepsy with cataplexy and in Europe for the treatment of alcohol withdrawal and narcolepsy. However, the illicit use and abuse of GHB occurs due to its sedative/hypnotic and euphoric effects. Sex differences in drug elimination pathways contribute to inter-individual variability observed between sexes with respect to drug disposition and effect. Our previous results demonstrated that GHB toxicokinetics varies over the estrus cycle, and between males and females; however, there is an absence of information on how the individual female sex hormones influence GHB toxicokinetics.