Date of Award

2018

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Melanie Felmlee

First Committee Member

Miki S. Park

Second Committee Member

Roshanak Rahimian

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. Monocarboxylate transporters (MCTs and SMCTs) are integral membrane proteins that control the bidirectional transport of endogenous substrates including lactate, acetate and pyruvate. They have also been found to transport and mediate the clearance and distribution of GHB. MCTs demonstrate a wide tissue distribution, including 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 the wide range of 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. The objective of this study was to evaluate sex differences and the influence of the estrus cycle on GHB toxicokinetics after IV administration. Our hypothesis is that renal clearance and toxicokinetics will vary over

the estrus cycle. Estrus cycle stage in female rats was determined by vaginal lavage prior to GHB administration. Ovariectomized (OVX) females were included in the study to evaluate GHB toxicokinetics in the absence of female sex hormones. Our results demonstrated that sex and the estrus cycle influence GHB toxicokinetics. Total and renal clearance varies over the estrus cycle with the highest renal clearance observed in proestrus females. In contrast, males and OVX females demonstrated significantly lower renal clearance. These results suggest that GHB toxicity and risk of overdose varies over the estrus cycle due to expression changes in renal MCTs and SMCTs. 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.

Pages

57

Available for download on Saturday, March 19, 2022

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