title: Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine(pyridine)chloroplatinum(II) and oxaliplatin in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, San Francisco, California 94158, USA.
authors.forename: Shuanglian
authors.initials: S
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Shuzhong
authors.initials: S
authors.lastname: Zhang
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027702:Organic Cation Transporter 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*; D000077150:Oxaliplatin; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D027702:Organic Cation Transporter 1; D009944:Organoplatinum Compounds; C530333:cis-diammine(pyridine)chloroplatinum(II); D000077150:Oxaliplatin