Role of Sex Hormones and Puberty on GHB Toxicokinetics and Monocarboxylate Transporter Regulation

Author

Qing Zhang, University of the PacificFollow

Date of Award

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Melanie Felmlee

First Committee Member

Miki S. Park

Second Committee Member

James A. Uchizono

Third Committee Member

Roshanak Rahimian

Fourth Committee Member

Bridget L. Morse

Abstract

Gamma-hydroxybutyric acid (GHB) is an endogenous short-chain fatty acid with clinical applications, primarily marketed as Xyrem, for the management of cataplexy and excessive daytime sleepiness in patients with narcolepsy. Despite its therapeutic uses, GHB is predominantly recognized for its illicit utilization, attributed to its sedative, hypnotic, and euphoric properties. It is frequently misused in contexts such as bodybuilding, recreational activities, and drug-facilitated sexual assault. The toxicokinetics of GHB exhibit nonlinearity in both humans and animal models, characterized by a reduced total clearance at increased doses due to capacity-limited metabolism and renal excretion, which leads to increased plasma concentrations. In cases of overdose, renal clearance becomes the predominant elimination pathway as metabolic processes become saturated. The tissue uptake and renal reabsorption of GHB is mediated by proton- and sodium-dependent monocarboxylate transporters, including MCTs (SLC16A) and SMCTs (SLC5A). Previous investigations in our laboratory have explored sex differences in the toxicokinetics of GHB at doses of 600 mg/kg and 1000 mg/kg in rats, and transporter expression revealing significant variations in MCT/SMCT expression in the liver and kidney. These findings suggest that sex hormones may influence MCT/SMCT expression in drug disposition tissues, thereby affecting GHB toxicokinetics. The present study aimed to further elucidate this relationship through three specific objectives: (1) To assess the impact of male sex hormone testosterone on GHB toxicokinetics at doses of 1000 mg/kg and 1500 mg/kg administered intravenously, following sex and cross-sex hormone treatment, with and without an MCT inhibitor. (2) To evaluate blood-brain barrier expression levels of MCT1 and CD147 membrane proteins in response to sex and cross-sex hormone treatments. (3) To evaluate hepatic expression levels of MCT1, MCT4, and CD147 membrane proteins following sex and cross-sex hormone treatments. We have demonstrated GHB toxicokinetics and toxicodynamics were significant altered following male sex and cross-sex hormone treatment. Testosterone-treated CST rats are more susceptible to GHB-induced toxicity at 1500 mg/kg dosage due to increased systemic exposure, decreased renal clearance, and increased sedative effects. Significant differences in metabolic clearance were observed following 1000 mg/kg and 1500 mg/kg GHB suggesting altered regulation of the underlying clearance pathways. Treatment with AR-C 155858 effectively mitigated GHB toxicity across all studied groups, underscoring its therapeutic potential in reversing GHB-induced adverse effects. Additionally, we have discovered that the BBB membrane-bound protein expression of CD147, as well as hepatic CD147 membrane-bound protein expression, may remain unaffected by sex or cross-sex hormone treatments. BBB MCT1 membrane-bound protein expressions were significantly altered in response to sex and cross-sex hormones in OVX (ovariectomized female rats, ovary removal surgery performed) animals only but not CST (castrated male rats, testicles removal surgery performed) animals. Hepatic MCT1 membrane-bound protein expressions were significantly altered in response to sex and cross-sex hormones in both OVX and CST rats. Hepatic MCT4 membrane-bound protein expression was specifically modified by female sex hormones. The regulatory mechanisms of MCT expression by sex hormones appear to be transporter specific. Animals that underwent gonadectomy before or after puberty displayed distinct regulatory responses of MCTs to subsequent hormone treatments. In future research, the impact of sex hormones on GHB-related metabolic enzymes should be investigated to elucidate the mechanisms underlying the observed alterations in metabolic clearance. Evaluating the expression of sex hormone receptors and correlating these findings with transporter expression, along with analyzing the effects of sex and cross-sex hormone replacement in conjunction with sex hormone receptor antagonists, will provide further insight into the regulatory mechanisms of MCTs in response to sex hormones. Additionally, the mechanisms through which puberty influences MCT gene regulation require further investigation to enhance our understanding of these complex interactions.

Pages

284

Recommended Citation

Zhang, Qing. (2025). Role of Sex Hormones and Puberty on GHB Toxicokinetics and Monocarboxylate Transporter Regulation. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/4304