Role of Organic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cis-Diammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice
Year: 2010
Type: article
Abstract: 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.
Source: Pharmaceutical Research
Institution: University of California, San Francisco
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,690
Funders: Tobacco-Related Disease Research Program, National Institutes of Health, University of California, San Francisco, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Liver Center, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
OpenAlex ID: W2053733750