Antiepileptic drug transport at the blood-brain barrier, the role of the SLC transporter family

Jones, Hayley Antiepileptic drug transport at the blood-brain barrier, the role of the SLC transporter family. PhD thesis, University of Liverpool.

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Abstract

The transporter hypothesis has been postulated to explain pharmacoresistance in epilepsy. Despite over a decade of research surrounding the drug transporter hypothesis, the role that solute carrier (SLC) transporters might play in this theory remains largely unaddressed. Hence, the major focus of this thesis was to investigate and identify SLC transporter systems of interest that are expressed at the blood-brain barrier (BBB) and to determine which, if any, of commonly prescribed antiepileptic drugs (AEDs) are substrates for such transporter systems. Characterisation of AED transport was undertaken using widely reported model systems such as Xenopus laevis oocytes and the human cerebral microvascular endothelial cell line (hCMEC/D3), together with novel stably-transfected MDCK II cell lines. Organic anion transporter 1A2 (OATP1A2), the monocarboxylate transporter (MCT) family and the organic anion transporter (OAT) family were specifically selected for investigation. Valproic acid and gabapentin showed the greatest evidence for SLC-mediated transport by OAT1/OAT3 and MCT1 respectively, while other compounds were largely unremarkable in this respect. Valproic acid transport increased OAT1 overexpressing cells compared to control but decreased in OAT3 overexpressing cells. Gabapentin uptake increased in MCT1 transfected Xenopus laevis oocytes and was shown to decrease in hCMEC/D3 cells in the presence of a panel of MCT inhibitors. The induction/suppression of expression of SLC transporters by AEDs was explored in the hCMEC/D3 cell line, in an attempt to understand how AEDs might influence the functionality of endogenous transport pathways. A number of AEDs were observed to induce/suppress expression of transporter genes involved in transport and detoxification. A further study explored the fundamental physiochemical properties of AEDs, which is relevant to their penetration into the brain. A number of AEDs, including lamotrigine, gabapentin and topiramate, observe adequate uptake in the hCMEC/D3 model of the BBB despite having physiochemical properties, such as a high polar surface area and negative log D value which may limit passive entry into the brain. This would suggest that a carrier mediated system may be involved in the uptake of these drugs into the brain. The work described in this thesis has shown that a number of AEDs may be subject to carrier mediated uptake into the brain. Individual differences in transporter expression at the BBB may be responsible for variability in brain concentrations of AEDs. However, at present, this does not provide us with an adequate explanation for why some people with epilepsy experience pharmacoresistant seizures.

Item Type:	Thesis (PhD)
Additional Information:	Date: 2014-10-06 (completed)
Subjects:	?? RM ??
Depositing User:	Symplectic Admin
Date Deposited:	20 Aug 2015 09:35
Last Modified:	17 Dec 2022 01:27
DOI:	10.17638/02010815
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2010815