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Fampridine is a Substrate and Inhibitor of Human OCT2, but not of Human MATE1, or MATE2K

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Abstract

Purpose

The renal clearance of fampridine (Fampyra®, or Ampyra®) significantly exceeds the glomerular filtration rate, suggesting active renal secretion is likely the major elimination pathway. The goal of this study was to identify the renal transporters that are involved in the renal active secretion, and elucidate the active renal secretion mechanism of fampridine.

Methods

The uptake of fampridine to HEK-293 cells overexpressing human OCT2, MATE1 or MATE2K was determined in the absence and presence of Cimetidine, the prototypical inhibitor of the transporters. The inhibition potential of fampridine on the renal transporters was evaluated by determining the uptake of TEA and Metformin, the probe substrates of the transporters of OCT2 and MATEs, respectively, in the absence or presence of fampridine.

Results

Significant time- and concentration-dependent uptake of fampridine by human OCT2 was observed. The Km and Vmax were determined as 51.0 ± 17.1 μM and 1107 ± 136 pmole/min/106 cells, respectively. Fampridine also inhibited OCT2 mediated uptake of Metformin with estimated IC50 of 66.8 μM. In contrast, there was not significant uptake of fampridine by human MATE1 or MATE2K, and fampridine did not inhibit MATE1 or MATE2K mediated uptake of TEA.

Conclusion

The studies indicated fampridine is a substrate and inhibitor of OCT2, but not MATE1 or MATE2K. Results from the study suggested the active renal secretion of fampridine is mediated by human OCT2 but not MATE1 or MATE2K. To our knowledge, fampridine is the first reported substrate specific to OCT2 but not to MATE1 or MATE2K.

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Authors and Affiliations

  1. Department of Drug Metabolism and Pharmacokinetics, Takeda, 35 Landsdowne St, Cambridge, Massachusetts, 02139, USA

    Guangqing Xiao

  2. Department of Drug Metabolism and Pharmacokinetics, Biogen, Cambridge, Massachusetts, 02142, USA

    Christopher Rowbottom

  3. BDPK, Intellia Therapeutics, Cambridge, Massachusetts, 02139, USA

    Carri Boiselle

  4. Foresee Pharmaceuticals Co., LTD, Taipei City, Taiwan, 22180, Republic of China

    Liang-Shang Gan

Authors
  1. Guangqing Xiao
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  2. Christopher Rowbottom
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  3. Carri Boiselle
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  4. Liang-Shang Gan
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Correspondence to Guangqing Xiao.

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Xiao, G., Rowbottom, C., Boiselle, C. et al. Fampridine is a Substrate and Inhibitor of Human OCT2, but not of Human MATE1, or MATE2K. Pharm Res 35, 159 (2018). https://doi.org/10.1007/s11095-018-2445-y

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  • DOI: https://doi.org/10.1007/s11095-018-2445-y

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