Pharmacokinetics and metabolism of an oligodeoxynucleotide phosphorothioate (GEM91®) in cynomolgus monkeys following intravenous infusion

被引:37
作者
Grindel, JM
Musick, TJ
Jiang, ZW
Roskey, A
Agrawal, S
机构
[1] Hybridon Inc, Cambridge, MA 02139 USA
[2] Covance Inc, Madison, WI 53704 USA
来源
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT | 1998年 / 8卷 / 01期
关键词
D O I
10.1089/oli.1.1998.8.43
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The pharmacokinetics and metabolism of an antisense oligonucleotide phosphorothioate (GEM91(R)) were studied in cynomolgus monkeys following intravenous infusion. [S-35]-Labeled GEM91 was administered to 12 monkeys by means of a 2-hour intravenous infusion at a dose of 4 mg/kg. Plasma pharmacokinetic analysis revealed that the maximum plasma concentration was 41.7 mu g equivalents/ml, which was achieved in 2.13 hours. The plasma elimination half-life was 55.8 hours based on radioactivity levels. Urinary excretion represented the major pathway of elimination, with 70% of the administered dose excreted in urine over 240 hours. The oligonucleotide was widely distributed to tissues. The highest concentrations were observed in the liver and kidney. Analysis of the extracted oligonucleotide following post-labeling with [P-32] on polyacrylamide gel electrophoresis showed the presence of both intact and degraded oligonucleotide in plasma, kidney, liver, spleen, and lymph nodes. Based on the methods used for post-labeling (either 3'-end or 5'-end), different patterns of bands were observed on polyacrylamide gel electrophoresis, suggesting metabolic modification of the administered oligonucleotide.
引用
收藏
页码:43 / 52
页数:10
相关论文
共 37 条
  • [1] PHARMACOKINETICS, BIODISTRIBUTION, AND STABILITY OF OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATES IN MICE
    AGRAWAL, S
    TEMSAMANI, J
    TANG, JY
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (17) : 7595 - 7599
  • [2] In vivo pharmacokinetics of phosphorothioate oligonucleotides containing contiguous guanosines
    Agrawal, S
    Tan, WT
    Cai, QY
    Xie, XW
    Zhang, RW
    [J]. ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT, 1997, 7 (03): : 245 - 249
  • [3] Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: In vitro and in vivo studies
    Agrawal, S
    Jiang, ZW
    Zhao, QY
    Shaw, D
    Cai, QY
    Roskey, A
    Channavajjala, L
    Saxinger, C
    Zhang, RW
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (06) : 2620 - 2625
  • [4] Agrawal S, 1997, CIBA F SYMP, V209, P60
  • [5] Antisense oligonucleotides: Towards clinical trials
    Agrawal, S
    [J]. TRENDS IN BIOTECHNOLOGY, 1996, 14 (10) : 376 - 387
  • [6] ABSORPTION, TISSUE DISTRIBUTION AND IN-VIVO STABILITY IN RATS OF A HYBRID ANTISENSE OLIGONUCLEOTIDE FOLLOWING ORAL-ADMINISTRATION
    AGRAWAL, S
    ZHANG, XS
    LU, ZH
    ZHAO, H
    TAMBURIN, JM
    YAN, YM
    CAI, HY
    DIASIO, RB
    HABUS, I
    JIANG, ZW
    IYER, RP
    YU, D
    ZHANG, RW
    [J]. BIOCHEMICAL PHARMACOLOGY, 1995, 50 (04) : 571 - 576
  • [7] PHARMACOKINETICS OF ANTISENSE OLIGONUCLEOTIDES
    AGRAWAL, S
    TEMSAMANI, J
    GALBRAITH, W
    TANG, JY
    [J]. CLINICAL PHARMACOKINETICS, 1995, 28 (01) : 7 - 16
  • [8] AGRAWAL S, 1997, ANTISENSE OLIGODEOXY, P57
  • [9] Agrawal S., 1996, ANTISENSE THERAPEUTI
  • [10] AGRAWAL S, 1996, ANTISENSE THERAPEUTI, P247