ABSTRACT
Gamma-hydroxybutyrate (GHB), is a popular drug of abuse utilized at raves and in drug-facilitate sexual
assault due to its’ euphoric, aphrodisiac, and sedative effects. The annual number of GHB-associated deaths
has continued to increase since the 1990s in the United States, the United Kingdom, Western Europe and
Australia. In the last decade the use of GHB has been increasing in the LBGTQ community due to the prevalence
of a phenomenon referred to as chemsex. Of the drugs used for chemsex, GHB is the most likely to cause acute
overdose. Proton- and sodium-dependent monocarboxylate transporters (MCTs/SMCTs) are involved in the
transport of GHB across biologically important barriers and tissues, and their expression governs GHB renal
clearance and brain distribution. Preliminary data demonstrates that GHB toxicokinetics (plasma concentrations
and renal clearance) are altered in the presence and absence of female sex hormones. Further, we have
demonstrated that male and female sex hormones regulate monocarboxylate transporters in the kidney, and
differences in GHB renal clearance over the estrous cycle, and between males and females are consistent with
the changes in renal monocarboxylate transporter expression. Despite the potential for sex hormones to regulate
GHB renal clearance and tissue distribution, there is a paucity of information in the literature regarding the
influence of sex and cross-sex hormone treatment on GHB toxicokinetics and toxicity. The focus of this
application is on investigating GHB toxicokinetics in response to sex and cross-sex hormone therapy and
identifying the sex hormone-dependent mechanisms regulating expression of renal and blood brain barrier (BBB)
monocarboxylate transporters. Our overall hypothesis is that variability in GHB toxicokinetics and overdose risk
result from sex hormone-dependent regulation of monocarboxylate transporters that govern GHB clearance and
distribution. We have proposed two specific aims to evaluate this hypothesis utilizing in vivo models of sex and
cross-sex hormone replacement, molecular biological and toxicokinetic techniques. The first specific aim
investigates GHB toxicokinetics and toxicity in response to sex and cross-sex hormone treatment. Our
hypotheses for this aim are that [1] GHB renal clearance and systemic exposure (AUC) will be altered in response
to individual male and female sex hormones; [2] males, and animals exposed to testosterone will have an
increased risk of acute overdose due to decreased renal clearance. In our second aim, we will investigate the
sex hormone-dependent regulation of renal and BBB MCTs and SMCTs. Our hypotheses are that sex and cross-
sex hormone treatment will differently regulate monocarboxylate transporter expression, and this regulation is
sex hormone receptor dependent. This proposal represents a novel extension of our previous work, and will
further our mechanistic understanding of sex hormone-dependent regulation of drug clearance, and the resultant
toxicokinetic consequences, and will help to identify populations with a greater risk of GHB overdose.
