(T1330-10-57) Female Sex Hormones Alter GHB Toxicokinetics

Purpose: 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Our previous results demonstrated that GHB toxicokinetics varies over the estrus cycle, and between males and females (unpublished data); however, there is an absence of information on how the individual female sex hormones influence GHB toxicokinetics . The objective of our study is to evaluate the influence of estrogen and progesterone on GHB toxicokinetics following sex and cross-sex hormone administration.

Methods: 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) 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 has significantly higher metabolic clearance than male and placebo-treated rats (P_OVX < 0.0001 and P<sub>CST < 0.0001).

Conclusion: Our results indicate that female sex hormones alter GHB toxicokinetics. Sex and cross-sex treatment significantly increased the total clearance and decreased GHB plasma exposure. These results suggest that the cross-gender rats reverse GHB overdose, which may identify a lower risk of GHB overdose in the corresponding population. Future work will evaluate the influence of female sex hormones on MCTs expression in kidney and GHB related enzyme expression in liver to further explain the mechanisms underlying changes in GHB toxicokinetics.

References: Melanie A. Felmlee et.al. Concentration-Effect Relationships for the Drug of Abuse Gamma-Hydroxybutyric Acid. The Journal of Pharmacology and Experimental Therapeutics. 2010.
Morris ME, Felmlee MA. Overview of the proton-coupled MCT (SLC16A) family of transporters: characterization, function and role in the transport of the drug of abuse gamma-hydroxybutyric acid. AAPS J. 2008;10(2):311-21.
Morse BL, Vijay N, Morris ME. gamma-Hydroxybutyrate (GHB)-induced respiratory depression: combined receptor-transporter inhibition therapy for treatment in GHB overdose. Mol Pharmacol. 2012;82(2):226-35.
Cao J, Ng M, Felmlee MA. Sex Hormones Regulate Rat Hepatic Monocarboxylate Transporter Expression and Membrane Trafficking. J Pharm Pharm Sci. 2017;20(1):435-44.

Acknowledgements: Funding for this project was provided by NIDA/NIGMS DA052120.


Figure 1: Area under the plasma concentration-time profile (AUC) (A and B) and total clearance (C and D) following administration of 1000 mg/kg iv in OVX and CST with estrogen, progesterone or both treatment and females (estrus) and males. Data are presented as mean ± SD, N = 5 - 6. (A) *P < 0.05 compared with males, (B) * P < 0.05 compared with males, (C) *P < 0.05 compared with males, (D) * P < 0.05 compared with males.


Figure 2: Renal clearance (A and B) and fraction of drug eliminated in urine (C and D) following administration of 1000 mg/kg iv in OVX (A) and CST (B) with estrogen, progesterone or both treatment and females (estrus) and males. Data are presented as mean ± SD, N = 5 - 6. (A) *P < 0.05 overall, (C) *P < 0.05 compared with OVX Estrogen Placebo, # P < 0.05 compared with OVX Progesterone Placebo, (D) *P < 0.05 compared with CST Estrogen, # P < 0.05 compared with female (estrus).


Figure 3: Metabolic clearance following administration of 1000 mg/kg iv in OVX and CST with estrogen, progesterone or both treatment and females (estrus) and males. Data are presented as mean ± SD, N = 5 - 6. (A) *P < 0.05 compared with OVX combo, # P < 0.05 compared with female (estrus), (B) *P < 0.05 compared with female (estrus), # P < 0.05 compared with CST combo.