P212 Fampridine is a substrate and inhibitor of human OCT2, but not MATE1 and MATE2K

Christopher Rowbottom , Biogen Idec, Cambridge, MA
Carri Boiselle , Biogen, Cambridge, MA
Lawrence Gan , BiogenIdec, Cambridge, MA
Tonika Bohnert , Biogen, Cambridge, MA
Guangqing Xiao , Biogen, Cambridge, MA
Title: Fampridine is a substrate and inhibitor of human OCT2, but not MATE1 and MATE2K

Objective: Fampridine (4-Aminopyridine, Famprya, or Ampyra) is an approved drug for the treatment of multiple sclerosis (MS). Clinical studies indicate that the renal clearance of Fampridine is 370 mL/min (EU SmPC), far exceeds the glomerular filtration rate (GFR), which suggested the renal active secretion is the major elimination pathway of clearance. The objective of the study is to assess the potential of renal drug transporter mediated drug-drug interactions.

Method: HEK293 cells over-expressing human OCT2, MATE1 or MATE2K were used in the study. Whether Fampridine is a substrate of the transporters was examined by determining the uptake in the single transfected or mock cells, in the absence or presence of a prototypical inhibitor of each transporter. The inhibition potential of Fampridine on the transporters was evaluated by determining the transporter-mediated uptake of a probe substrate for each transporter in the absence or presence of Fampridine.

Conclusion: Fampridine as a substrate of OCT2 is demonstrated in the study. Significant transporter mediated uptake in OCT2-expressing cells over the mock cells was observed, and was inhibited by the OCT2 prototypical inhibitor, Cimetidine. In addition, the uptake of Fampridine by OCT2 was time and concentration dependent, further confirming the uptake was a carrier mediated process with a Km of 51.0 µM and Vmax of 1107 pmol/min/10-6 cells. Fampridine as an inhibitor of OCT2 was also demonstrated in the study. The transporter-mediated uptake of the OCT2 probe substrate Metformin to OCT2-expressing cells was inhibited in the presence of Fampridine in a concentration dependent manner with an IC50 value of 66.8 µM. In contrast to OCT2, Fampridine is characterized neither a substrate nor an inhibitor of MATE1 or MATE2K. There was no significant difference on the uptake of Fampridine to MATE1/ MATE2K expressing cells or mock cells, in the absence or presence of the prototypical inhibitor Cimetidine. Fampridine did not show marked effect on MATE1/MATE2K mediated uptake of TEA. To our knowledge, this is the first report of a specific substrate to OCT2 but not MATE1 or MATE2K.