TY - JOUR
T1 - In vivo stability, disposition and metabolism of a "hybrid" oligonucleotide phosphorothioate in rats
AU - Zhang, Ruiwen
AU - LU, Zhihong
AU - Zhao, Hui
AU - Zhang, Xueshu
AU - Diasio, Robert B.
AU - Habus, Ivan
AU - Jiang, Zhiwei
AU - Iyer, Radhakrishnan P.
AU - Yu, Dong
AU - Agrawal, Sudhir
PY - 1995/8/8
Y1 - 1995/8/8
N2 - Oligodeoxynucleotide phosphorothioates containing segments of 2′-O-methyloligoribo-nucleotide phosphorothioates at both 3′- and 5′-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined oligodeoxynucleotide phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.
AB - Oligodeoxynucleotide phosphorothioates containing segments of 2′-O-methyloligoribo-nucleotide phosphorothioates at both 3′- and 5′-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined oligodeoxynucleotide phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.
KW - HIV
KW - antisense oligodeoxynucleotide phosphorothioate
KW - biostability
KW - metabolism
KW - pharmacokinetics
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U2 - 10.1016/0006-2952(95)00159-W
DO - 10.1016/0006-2952(95)00159-W
M3 - Article
C2 - 7646561
AN - SCOPUS:0029134526
SN - 0006-2952
VL - 50
SP - 545
EP - 556
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -