Influence of Female Sex Hormones on GHB Toxicokinetics and Regulation of MCTs and SMCTs

Author

Hao Wei, University of the PacificFollow

Date of Award

2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Melanie Felmlee

First Committee Member

William K. Chan

Second Committee Member

Miki S. Park

Third Committee Member

Roshanak Rahimian

Fourth Committee Member

Robert Jones

Abstract

Gamma-hydroxybutyric acid (GHB) is an endogenous shorty chain fatty acid that is used clinically as Xyrem to treat narcolepsy. GHB is best known for its illicit use and abuse due to its sedative/hypnotic and euphoric effects. It is used in body building, for recreational use and sexual assault. Nonlinear toxicokinetics of GHB has been described in humans and rats with decreased total clearance at higher doses due to capacity-limited metabolism resulting in a higher plasma exposure. Renal clearance increases with increasing dose and becomes the major route of GHB elimination in overdose cases due to saturation of GHB metabolism. Proton- and sodium-dependent monocarboxylate transporters (MCTs (SLC16A) and SMCTs (SLC5A)) have been identified as major transporters in the renal reabsorption of GHB moving it from filtrate back to systemic circulation. Our laboratory has previously investigated sex differences in GHB toxicokinetics at 600 mg/kg in rats and identified sex differences in MCT expression in the liver and kidney. These data suggest that individual sex hormones may be involved in altering MCT and SMCT expression in drug disposition tissues and as a result alter GHB toxicokinetics. The present study had three objectives:1) GHB toxicokinetics were evaluated over the estrous cycle, and in the presence and absence of sex hormones following a dose of 1000 mg/kg iv in rats; 2) The role of individual female sex hormones on altering GHB toxicokinetics was investigated at 1000 mg/kg and 1500 mg/kg iv following sex and cross-sex hormone treatment with 17β-estradiol and progesterone, alone or in combination; and 3) renal MCT1, MCT4, SMCT1 and CD147 mRNA and membrane protein expression were quantified in response to female sex and cross-sex hormone treatment. We have demonstrated that GHB toxicokinetics and renal clearance vary between sexes, over the estrus cycle in females and in the absence of female and male sex hormones. In hormone-treated animals, GHB toxicokinetics were altered following sex and cross-sex hormone treatment with significantly increased total clearance and decreased GHB plasma exposure at 1000 mg/kg. Significant differences in renal and metabolic clearance were observed following 1000 mg/kg and 1500 mg/kg GHB suggesting altered regulation of the underlying clearance pathways. Additionally, we have investigated the renal mRNA and membrane-bound protein expression of MCT1, MCT4, CD147 and SMCT1 which were significantly altered in response to female sex hormones in both OVX (ovariectomized female rats, ovary removal surgery performed) and CST (castrated male rats, testicles removal surgery performed) rats. The mechanisms underlying MCT/SMT regulation by female sex hormones appear to vary based on the specific transporter. The alteration of renal monocarboxylate transporters in response to female sex hormones may contribute to the observed differences in GHB toxicokinetics, which may benefit the potential antidotes of GHB as a combined therapeutic strategy in clinic. In future, inhibition studies should be performed with the coadministration of MCTs/SMCTs inhibitor with GHB to further confirm the contribution of monocarboxylate transporters to GHB toxicokinetics following sex and cross-sex hormone treatment. The influence of female sex hormones on GHB-related metabolic enzymes and monocarboxylate transporters in liver should be evaluated to further explore the mechanism of underlying the observed alterations in metabolic clearance. Sex hormone receptor expression should be evaluated by western bolt and correlated with transporter expression, combined with analysis of sex and cross-sex hormone replacement with coadministration of sex hormone receptor antagonists, to further elucidate the mechanisms underlying MCTs/SMCTs regulation in response to female sex hormones. Additionally, GHB TK studies should also be conducted, combined with sex and cross-sex hormone replacement with coadministration of sex hormone receptor antagonists, to further confirm the effect of sex hormone receptor antagonist in GHB toxicokinetics. The MCT/SMCT expression is a key determinant of their substrates’ drug disposition; sex differences and altered regulation in response to sex and cross-sex hormone treatment may contribute to differences in GHB toxicokinetics and toxicity.

Pages

164

Recommended Citation

Wei, Hao. (2023). Influence of Female Sex Hormones on GHB Toxicokinetics and Regulation of MCTs and SMCTs. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/4262