title: Pharmacokinetic Profile and Acute Toxicological Properties of a Novel Radiosensitizer Cytosine-Phosphate-Guanosine Oligodeoxynucleotide 107 in Mice Following Intravenous and Orthotopic Administration.
abstract: The synthetic cytosine-phosphate-guanosine oligodeoxynucleotide 107 (CpG ODN107) is a novel radiosensitizer for glioma treatment. However, the information related to its pharmacokinetics and toxicity remains unclear. Therefore, the plasma pharmacokinetics, distribution, elimination, and acute toxicity of CpG ODN107 in mice were investigated in the present experiments. The results from the liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed that the plasma elimination half-life (t1/2β) of CpG ODN107 in BALB/c mice varied slightly with the dose, and it was 0.65, 0.49, and 0.50 h at the intravenous doses of 2.5, 5, and 10 mg/kg, respectively. CpG ODN107 rapidly and widely distributed in organs/tissues, except the brain and testes. The highest concentrations were found in the liver (28.6% of the administered dose after 0.5 h) and the kidneys (5.7% of the administered dose after 1 h). CpG ODN107 (0.3, 3, and 30 μg/mL) could highly bind to human and mouse plasma proteins in vitro. CpG ODN107 in the forms of prototype was excreted in urine (1.79%) and feces (0.91%), and its shortened metabolites were excreted in urine (2.1%) and feces (2.2%) within the first 24 h. The mice in vivo optical image showed CpG ODN107 labeled with Alexa Fluor 680 fluorochrome (AF680) accumulated in the brain after orthotopic injection, eliminated very slowly, and excreted in urine compared with poly T labeled with AF680. The median lethal dose (LD50) of CpG ODN107 was 75.7 mg/kg for mice; this dose only could produce apparent spleen and liver damage, in line with the distribution features of CpG ODN. In conclusion, our present pharmacokinetic and toxicity investigation will provide helpful information to further pharmacodynamic and pharmacokinetic research of CpG ODN107 and other oligodeoxynucleotide drugs in the future.
authors.affiliation: 1 Department of Pharmacology, College of Pharmacy, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cen
authors.affiliation: 1 Department of Pharmacology, College of Pharmacy, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
authors.affiliation: 2 No. 546 Hospital of China People's Liberation Army , Urumqi, People's Republic of China .
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yin
authors.affiliation: 1 Department of Pharmacology, College of Pharmacy, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Zifei
authors.initials: Z
authors.lastname: Yan
authors.affiliation: 1 Department of Pharmacology, College of Pharmacy, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1 Department of Pharmacology, College of Pharmacy, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: 3 Biomedical Analysis Center, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Feng
authors.initials: F
authors.lastname: Pan
authors.affiliation: 1 Department of Pharmacology, College of Pharmacy, The Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D006207:Half-Life; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000493:pharmacokinetics* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: C576997:CpG ODN107; D009838:Oligodeoxyribonucleotides; D011838:Radiation-Sensitizing Agents