Female Sex Hormones Alter GHB Toxicokinetics
Poster Number
30
Introduction/Abstract
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 placebo for 21 days (N = 5 – 6 per group). GHB (1000 mg/kg or 1500 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 both female sex hormones alter GHB toxicokinetics. In cis-gender female rats, OVX estrogen, OVX progesterone, OVX combo and female (estrus) groups have significantly lower AUCs and total clearance than males at 1000 mg/kg of GHB IV dose. However, there is no difference between groups at 1500 mg/kg. Renal clearance and fe also shows significant difference at both 1000 mg/kg and 1500 mg/kg. However, OVX combo animals have the consistent trend with intact female (estrus) at 1000 mg/kg but not consistent at 1500 mg/kg. Metabolic clearance shows the significant higher value in OVX combo and intact female (estrus) at 1000 mg/kg. At 1500mg/kg, intact female and male groups have decreased metabolic clearance comparing to 1000mg/kg result while the other hormone replacement OVX groups have similar or increased metabolic clearance. In trans-gender animals, the trend is similar with cis-gender result. CST combo and intact female have significant decreased AUC and increased total clearance compared with males at 1000mg/kg. There is no significance in 1500 mg/kg results. The renal clearance and fe shows the similar trend and CST estrogen has the lowest renal clearance and fe at 1000 mg/kg. At 1500 mg, intact male and female (estrus) have increased renal clearance and fe comparing to them at 1000 mg/kg while the other hormone-treated groups show saturated renal clearance. There is significance in metabolic clearance as well. CST combo and intact female (estrus) have consistent higher value than intact female at 1000 mg/kg. At 1500 mg/kg, intact female and male groups have decreased metabolic clearance comparing to 1000mg/kg result while the other hormone replacement CST groups have similar or increased metabolic clearance, which is also consistent with cis-gender results.
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
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
Format
Poster Presentation
Female Sex Hormones Alter GHB Toxicokinetics
Library and Learning Center, 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.
