| Autor: |
Soucy, Nicole V., Riley, Jason P., Templin, Michael V., Geary, Richard, de Peyster, Ann, Levin, Arthur A. |
| Zdroj: |
Birth Defects Research Part B: Developmental and Reproductive Toxicology; February 2006, Vol. 77 Issue: 1 p22-28, 7p |
| Abstrakt: |
BACKGROUND: Fetal uptake of an antisense oligonucleotide was evaluated after intravenous (i.v.) dosing of ISIS 2105, a 20‐base phosphorothioate oligonucleotide, in timed‐pregnant Sprague‐Dawley rats. METHODS: To maximize the potential for fetal exposure, ISIS 2105 was administered as a 3‐hr infusion at 6.6 mg/kg/hr with a total dose of 20 mg/kg, or as a continuous 7‐day infusion at 0.35 mg/kg/hr with a total dose of 59 mg/kg. This dosing regime is higher than a patient would be expected to receive in the clinical use of oligonucleotides. Infusions were delivered through a jugular vein cannula by syringe pump on gestation day (GD) 19 (3‐hr exposure) or by osmotic pumps implanted subcutaneously (s.c.) starting on GD 12 (7‐day exposures). RESULTS: After a 3‐hr infusion, maternal and fetal plasma concentrations of ISIS 2105 were >100 µg/ml and <0.07 µg/ml, respectively with a maternal fetal ratio of >1,000. Maternal regions of the placenta had twice the oligonucleotide concentration compared to fetal regions of the placenta (6 µg/g vs. 3 µg/g). After this acute exposure the concentrations in fetal kidney and liver were approximately 140‐ and 500‐fold less than the maternal kidney and liver respectively. After 7‐day infusion maternal plasma concentrations were 0.82 µg/ml and fetal concentrations were <0.22 µg/ml. By capillary gel electrophoresis (CGE) only the fetal liver consistently had quantifiable oligonucleotide concentrations (range=1.01–4.95 µg/g) compared to a mean concentration of 50.11±1.71 µg/g in the maternal liver a maternal to fetal ratio of approximately 10:50 after 7 days of infusion. CONCLUSIONS: There was a low level of transfer from dam to fetus, consistent with a slow equilibrium but the permeability of placenta to this 6 kDa polyanionic compound seemed to be limited even at supraclinical doses. Birth Defects Res (Part B) 77:22–28, 2006. © 2006 Wiley‐Liss, Inc. |
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