Purpose(s)
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. Monocarboxylate transporters (MCTs and SMCTs) are integral membrane proteins that control the transport of GHB, and mediate its’ clearance and distribution. MCTs demonstrate a wide tissue distribution, including the brain, kidney, liver, and intestine, all of which play an important role in determining the disposition of GHB. Sex differences in drug elimination pathways contribute to inter-individual variability observed between sexes with respect to drug disposition and effect. Sex differences in MCT expression have been observed in the brain, muscle, liver and kidney with variations potentially driven by sex hormones; however, there is an absence of information on how these expression differences translate into sex differences in GHB toxicokinetics.
Method(s)
GHB toxicokinetics and renal clearance were evaluated in male, female estrus cycle stages, ovariectomized (OVX) female and castrated (CST) male Sprague-Dawley rats ( N = 5 – 6 per group).
Estrus cycle stage was determined in female rats by vaginal lavage prior to GHB administration. OVX and CST animals were included to evaluated GHB toxicokinetics in the absence of sex hormones.
GHB (600 mg/kg) was administered by intravenous bolus injection via the jugular vein cannula to all groups of rats. GHB concentration in plasma and urine was quantified using LC/MS/MS assay.
Non-compartmental analysis of the plasma-concentration time profiles was conducted in Phoenix WinNonLin.
MCT1 and SMCT1 membrane expression was identified by western blot with expression normalized to Na+K+ ATPase expression.
Result(s)
(Please see the poster)
Conclusion(s)
Our results demonstrate that GHB toxicokinetics and MCTs expression varies over the estrus cycle and in the absence of male and female sex hormone.
Future studies will evaluate higher GHB doses to determine the role of sex hormones in GHB overdose and fatality.
In addition, hormone replacement studies will be conducted to confirm the role of individual sex hormones on GHB toxicokinetics, and renal expression of monocarboxylate transporters.