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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.

Lung cancer is the second most common cancer in both men and women around the world, and 85% of it is non-small cell lung cancer (NSCLC). It is estimated that in 2020, there will be 228,820 cases of lung cancer and 135,720 deaths from lung (American Cancer Society, 2020). The prognosis of lung cancer is poor ( Traditionally, the most commonly used in vitro method for screening therapeutic drugs is monolayer cell cultures, which are reproducible, convenient and of low cost. However, monolayer cell culture models are unable to reproduce many properties of in vivo solid tumors such as the morphological features and the microenvironment including cellular heterogeneity, cell-cell interactions, and gradients of oxygen, pH, and nutrients. Consequently, excessive ineffective drug candidates would proceed to animal studies, which would prolong the time for drug development and increase the overall cost of drug discovery. In consideration of the foregoing, in vitro models of cancer based on three-dimensional multicellular spheroids (MCS) have been developed in our group to characterize drug candidates and drug delivery systems. Compared to monolayer cells, the multicellular spheroids can better simulate drug penetration and drug resistance in solid tumors. Therefore, the multicellular spheroids represent a more clinically relevant in vitro model to evaluate the efficacy of anticancer drugs. This project aims to characterize MCS of lung cancer cells as an improved platform to evaluate drug candidates against lung cancer. Cell viability assays on cisplatin, carboplatin, gemcitabine, and doxorubicin have been conducted to compare the anticancer activities between conventional monolayer cells and the corresponding MCS of human lung cancer cell lines, A549 and A549-iRFP (fluorescently labeled A549 cells). Higher concentrations of the tested anticancer drugs is consistently needed to inhibit 50% the cell viability in MCS than the corresponding monolayer cells of A549 and A549-iRFP. Cycled dosing schedules based on guidelines for NSCLC from National Comprehensive Cancer Network have been designed and used to treat A549-iRFP MCS. The A549-iRFP MCS have been exposed to anticancer drugs either continuously, or in pulsed concentrations according to the drugs’ pharmacokinetics (PK). The continuous drug exposure has been found to inhibit more cell growth in MCS than the corresponding PK-mimetic drug exposure. Such phenomenon would bring significant positive bias to the activity of many anticancer drug candidates during their early discovery and development. Taken together, MCS of A549 and A549 iRFP cells better represent the efficacy of anticancer drugs in clinic than the monolayer. MCS can also be used to evaluate anticancer drug candidates by pulsed drug exposure based on their pharmacokinetics, and by commonly used cycled dosing regiments to better predict their efficacy in clinical settings.