DMD Celsis microsomes mean better data

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leeds, J. M.
Right arrow Articles by Levin, A. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leeds, J. M.
Right arrow Articles by Levin, A. A.

Vol. 26, Issue 7, 670-675, July 1998

Pharmacokinetics of an Antisense Oligonucleotide Injected Intravitreally in Monkeys

Janet M. Leeds,1 Scott P. Henry,1 Steve Bistner, Scott Scherrill, Kevin Williams, and Arthur A. Levin

Isis Pharmaceuticals, Inc. (J.M.L., S.P.H., S.S., A.A.L.), University of Minnesota, College of Veterinary Medicine (S.B.), and Covance Laboratories (K.W.)

The kinetics of an intravitreally administered phosphorothioate oligonucleotide, ISIS 2922, were studied in cynomolgus monkeys. Vitreal and retinal concentrations were measured after administration of 11, 57, or 115 µg/eye. ISIS 2922 concentrations in vitreous and retina were compared, after single, weekly, or biweekly doses, for potential accumulation. ISIS 2922 levels were quantified using solid-phase extraction followed by capillary gel electrophoresis. Concentrations of ISIS 2922 in the vitreous were proportional to the dose and were nearly linear with respect to the dose. The ISIS 2922 concentrations 3 days after dosing ranged from 80 nM to approximately 1.5 µM. By 14 days after intravitreal injection, the concentrations were below the limit of quantitation (<10 nM) for all dose groups. There was no accumulation in the vitreous after multiple weekly or biweekly doses. The concentrations of ISIS 2922 in the retina 2 days after a single intravitreal injection ranged from 50 nM to 1.1 µM. The uptake and disposition of ISIS 2922 in the retina appeared to have been saturated between the 57- and 115-µg doses; the average concentrations were 0.71 ± 0.24 µM (N = 4) and 0.88 ± 0.27 µM (N = 3) for the two doses, respectively. Electrophoretic profiles of extracts revealed multiple chain-shortened oligonucleotides in the vitreous and retina, suggesting extensive metabolism in both compartments. Analyses from the multiple-dose study suggested that accumulation was dependent on the total administered dose, with accumulation occurring after biweekly dosing in the 115-µg dose group and only after weekly dosing in the 57-µg dose group.

1   Joint first authors.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Toxicol PatholHome page
B. G. Short
Safety Evaluation of Ocular Drug Delivery Formulations: Techniques and Practical Considerations
Toxicol Pathol, January 1, 2008; 36(1): 49 - 62.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
J. Gaudreault, D. Fei, J. Rusit, P. Suboc, and V. Shiu
Preclinical Pharmacokinetics of Ranibizumab (rhuFabV2) after a Single Intravitreal Administration
Invest. Ophthalmol. Vis. Sci., February 1, 2005; 46(2): 726 - 733.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
N. Mandava, P. Blackburn, D. B. Paul, M. W. Wilson, S. B. Read, E. Alspaugh, R. Tritz, J. R. Barber, J. M. Robbins, and C. A. Kruse
Ribozyme to Proliferating Cell Nuclear Antigen to Treat Proliferative Vitreoretinopathy
Invest. Ophthalmol. Vis. Sci., October 1, 2002; 43(10): 3338 - 3348.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
S. P. Henry, R. C. Miner, W. L. Drew, J. Fitchett, C. York-Defalco, L. M. Rapp, and A. A. Levin
Antiviral Activity and Ocular Kinetics of Antisense Oligonucleotides Designed to Inhibit CMV Replication
Invest. Ophthalmol. Vis. Sci., October 1, 2001; 42(11): 2646 - 2651.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
B. Detrick, C. N. Nagineni, L. R. Grillone, K. P. Anderson, S. P. Henry, and J. J. Hooks
Inhibition of Human Cytomegalovirus Replication in a Human Retinal Epithelial Cell Model by Antisense Oligonucleotides
Invest. Ophthalmol. Vis. Sci., January 1, 2001; 42(1): 163 - 169.
[Abstract] [Full Text]

Home page
 Drug Metab. Dispos.Home page
B. H. Dvorchik and J. K. Marquis
Disposition and Toxicity of a Mixed Backbone Antisense Oligonucleotide, Targeted against Human Cytomegalovirus, after Intravitreal Injection of Escalating Single Doses in the Rabbit
Drug Metab. Dispos., October 1, 2000; 28(10): 1255 - 1261.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
L. Q. Sun, M. J. Cairns, E. G. Saravolac, A. Baker, and W. L. Gerlach
Catalytic Nucleic Acids: From Lab to Applications
Pharmacol. Rev., September 1, 2000; 52(3): 325 - 348.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
W.-Y. Shen, K. L Garrett, L. da Cruz, I. J Constable, and P. E Rakoczy
Dynamics of phosphorothioate oligonucleotides in normal and laser photocoagulated retina
Br. J. Ophthalmol., July 1, 1999; 83(7): 852 - 861.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.