caa a22 4500 445312904 CHVBK 20180317142636.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s11095-010-0312-6 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0312-6 Role of Organic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cis -Diammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice [Elektronische Daten] [Shuanglian Li, Ying Chen, Shuzhong Zhang, Swati More, Xiaozhu Huang, Kathleen Giacomini] 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 ± 0.0391ml/min*kg versus 0.649 ± 0.0807ml/min*kg in wild-type mice, p < 0.05) and volume distribution (1.90 ± 0.161L/kg versus 3.37 ± 0.196L/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. The Author(s), 2010 OCT1 nationallicence pharmacokinetics nationallicence platinum agent nationallicence toxicity nationallicence transporter nationallicence ABC : ATP Binding Cassette nationallicence CDPCP : cis-Diammine(pyridine)chloroplatinum(II) nationallicence FBS : fetal bovine serum nationallicence GAPDH : glyceraldehydes-3-phosphate dehydrogenase nationallicence ICP-MS : inductively coupled plasma mass spectrometry nationallicence ITS : insulin-transferrin-selenium nationallicence Kim-1 : kidney injury molecule-1 nationallicence MPP+ : N-methylquinine, and 1-methyl-4-phenylpyridinium nationallicence OCTs : organic cation transporters nationallicence PK : pharmacokinetics nationallicence qRT-PCR : quantitative real-time polymerase chain reaction nationallicence SLC : solute carrier nationallicence TEA : tetraethylammonium nationallicence Li Shuanglian Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut Chen Ying Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut Zhang Shuzhong Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut More Swati Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut Huang Xiaozhu Lung Biology Center, University of California, 94143, San Francisco, California, USA aut Giacomini Kathleen Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 610-625 0724-8741 28:3<610 2011 28 11095 https://doi.org/10.1007/s11095-010-0312-6 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0312-6 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Li Shuanglian Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut NATIONALLICENCE 700 1- Chen Ying Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut NATIONALLICENCE 700 1- Zhang Shuzhong Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut NATIONALLICENCE 700 1- More Swati Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut NATIONALLICENCE 700 1- Huang Xiaozhu Lung Biology Center, University of California, 94143, San Francisco, California, USA aut NATIONALLICENCE 700 1- Giacomini Kathleen Department of Bioengineering and Therapeutic Sciences, University of California, 1550 4th Street, 94158, San Francisco, California, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/3(2011-03-01), 610-625 0724-8741 28:3<610 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer