Pharmacokinetics and Drug Transport

The in vivo sampling method microdialysis is an important tool in providing accurate information on the pharmacokinetics, metabolism and transport of various drugs. Pharmacokinetics data such, as absorption and metabolism of pharmaceuticals are crucial in drug development. It is important to know if a compound is absorbed, how long it takes to be absorbed and how it is distributed in order to better understand its mechanism of action. Microdialysis sampling is an effective tool for measuring in vivo drug concentrations in virtually any tissue in the body. Microdialysis probes contain a semi-permeable membrane, which allows for diffusion of the drug from the tissue into the probe for analysis.

Models and Treatments for Epilepsy

Epilepsy is a condition that affects approximately 1% of the world population. Of this population, an estimated 40% are resistant to current treatments. This has prompted numerous attempts to create other viable treatments for this condition. Key to the success of these treatments is the basic knowledge of the neurochemical events that occur. 3-mercaptopropionic acid (3-MPA) can be used to chemically create a seizure model in rats by enhancing excitation in the brain. The pharmacokinetics of 3-MPA are not known, but would serve as an important independent variable in assessing its pharmacodynamic properties.

The purpose of this research was to develop a method using microdialysis sampling in combination with electrophysiological techniques to study the pharmacokinetic-pharmacodynamic relationship within the brain after the administration of 3-MPA. Microdialysis samples were collected in vivo at a perfusion rate of 1 μL/min over 5 minute intervals. The dialysates were then analyzed by HPLC with either fluorescence or electrochemical detection. The components of interest were the amino acid neurotransmitters glutamate (Glu) and γ-aminobutyric acid (GABA), the main excitatory and inhibitory neurotransmitters, respectively, and the convulsant 3-MPA.

Detection limits for Glu and GABA in microdialysates are 13 nM and 6 nM, respectively. This is well below the basal concentrations of Glu and GABA of 5-20 μM. The detection limit for 3-MPA is 500 nM in microdialysate. A steady state of seizure activity was obtained using a constant infusion of the convulsant, and there was on average a 100% increase in Glu (n = 5) and a 50% decrease in GABA (n = 5). Also, a marked increase in the electroencephalographic (EEG) response (frequency and amplitude) was noticed over the entirety of the experiment. The results from these experiments demonstrated microdialysis to be useful in monitoring the pharmacokinetics of 3-MPA in vivo as well as the associated neurochemical changes.

Effects of a Potential Addiction Pharmacotherapy on Brain Neurochemistry

The overall objective of this project is to investigate S-(N, N-diethyl-carbamoyl) glutathione (SDEG or carbamathione) as a possible therapeutic agent in alcohol and cocaine addiction. In particular, we will investigate the effect of carbamathione on the brain neurotransmitters. Microdialysis probes will be implanted into the jugular vein and in the brain to monitor levels of carbamathione, GABA, glutamate and various other neurotransmitters using NDA/CN derivatization and CE-LIF. Another goal of this project is to investigate the mechanism by which carbamathione crosses the blood-brain barrier (BBB). Carbamathione is a metabolite of disulfiram, a drug used in the treatment of alcohol addiction. Previous studies in our lab show that carbamathione crosses the BBB upon administration of disulfiram, S-methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO) and carbamathione. Disulfiram and DETC-MeSO were not found in the brain. Since carbamathione is a glutathione adduct, a glutathione transferase type of transporter has been suggested to be involved.

Another aim of this project is to elucidate the pharmacokinetics of carbamathione distribution in the liver, the blood and the brain. The metabolism of disulfiram and DETC-MeSO in the liver will be monitored to gain information on the percentage of carbamathione that is produced from its precursors as well as to investigate its site of formation as it is transported to the brain. One long-term goal of this project is to extend the study of brain neurotransmitters to awake animals and correlate behavioral changes with changes in brain neurochemistry. This would help provide a better understanding of addiction as well as provide a tool to assess potential drugs against various forms of addiction.

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