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.
Bibliographical noteFunding Information:
This study was supported by a grant from the National Institutes of Health, GM36780 and a Grant from the TRDRP grant 17RT-0126. This work was also made possible in part by core service provided by UCSF liver center (NIH P30 DK26743). Y.C. was supported by National Research Service Award T32 GM07546 from the National Institutes of Health. We acknowledge the services provided by Mouse Pathology Core of UCSF Helen Diller Family Comprehensive Cancer Center, the J David Gladstone Histology and Microscopy core and the Clinical Laboratory of the San Francisco General Hospital. We also thank Rob Franks at the Institute of Marine Sciences of University of California, Santa Cruz, for his great help in analyzing platinum using ICP-MS.