Lamotrigine is a substrate for OCT1 in brain endothelial cells.

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Dickens D, Owen A, Alfirevic A, Giannoudis A, Davies A, Weksler B, Romero IA, Couraud PO, Pirmohamed M

Lamotrigine is a substrate for OCT1 in brain endothelial cells.

Biochem Pharmacol. 2012 Mar 15;83(6):805-14. doi: 10.1016/j.bcp.2011.12.032. Epub 2011 Dec 29.

PubMed ID

22227272 [ View in PubMed

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Abstract

The mechanisms that underpin the passage of lamotrigine at the blood-brain barrier to its site of action in the brain is poorly understood. Lamotrigine has been postulated to be delivered to its site of action in the brain favourably despite its physicochemical properties. The aim of this study was to investigate the transport of lamotrigine in an in-vitro model of the BBB. In this study, lamotrigine was found to have a distribution coefficient of 0 at pH 7.4 indicating that it was not highly lipophilic. Human brain endothelial cells (hCMEC/D3) were used to probe the interaction of lamotrigine with drug transporters. The uptake of lamotrigine into hCMEC/D3 cells was found to be an active process (K(m) = 62 +/- 14 muM; V(max) = 385 +/- 30 pmol/min/million cells). Furthermore, use of a panel of transporter inhibitors indicated that this active uptake was mediated by organic cation transporter 1 (OCT1). OCT1 mRNA and protein were shown to be expressed in hCMEC/D3 cells. KCL22 cells overexpressing OCT1 were then used to validate these findings. Lamotrigine was confirmed to be a substrate and inhibitor in OCT1-transfected KCL22 cells. A putative pharmacokinetic drug-drug interaction (DDI) between quetiapine and lamotrigine was recently reported in patients and we show here that quetiapine is a potent inhibitor of the OCT1-mediated transport of lamotrigine. This is the first time that a specific influx transporter has been shown to transport lamotrigine. The clinical implications of these findings with respect to the efficacy of lamotrigine and its potential for DDI require further investigation.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Lamotrigine	Solute carrier family 22 member 1	Protein	Humans	Unknown	Substrate	Details