Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine(pyridine)chloroplatinum(II) and oxaliplatin in mice

Pharm Res. 2011 Mar;28(3):610-25. doi: 10.1007/s11095-010-0312-6. Epub 2010 Nov 23.


Purpose: The goal of this study was to test the hypothesis that by controlling intracellular uptake, organic cation transporter 1, Oct1 is a key determinant of the disposition and toxicity of cis-diammine(pyridine)chloroplatinum(II)(CDPCP) and oxaliplatin.

Methods: Pharmacokinetics, tissue accumulation and toxicity of CDPCP and oxaliplatin were compared between Oct1-/- and wild-type mice.

Results: After intravenous administration, hepatic and intestinal accumulation of CDPCP was 2.7-fold and 3.9-fold greater in Oct1 wild-type mice (p < 0.001). Deletion of Oct1 resulted in a significantly decreased clearance (0.444 ± 0.0391 ml/min*kg versus 0.649 ± 0.0807 ml/min*kg in wild-type mice, p < 0.05) and volume distribution (1.90 ± 0.161 L/kg versus 3.37 ± 0.196 L/kg in wild-type mice, p < 0.001). Moreover, Oct1 deletion resulted in more severe off-target toxicities in CDPCP-treated mice. Histologic examination of the liver and measurements of liver function indicated that the level of hepatic toxicity was mild and reversible, but was more apparent in the wild-type mice. In contrast, the effect of Oct1 on the pharmacokinetics and toxicity of oxaliplatin in the mice was minimal.

Conclusions: Our study suggests that Oct1 plays an important role in the pharmacokinetics, tissue distribution and toxicity of CDPCP, but not oxaliplatin.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Organic Cation Transporter 1 / deficiency
  • Organic Cation Transporter 1 / genetics
  • Organic Cation Transporter 1 / physiology*
  • Organoplatinum Compounds / pharmacokinetics*
  • Organoplatinum Compounds / toxicity*
  • Oxaliplatin
  • Tissue Distribution / drug effects
  • Tissue Distribution / physiology


  • Organic Cation Transporter 1
  • Organoplatinum Compounds
  • cis-diammine(pyridine)chloroplatinum(II)
  • Oxaliplatin