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Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice.
Antisense Nucleic Acid Drug Dev. 2000 Oct; 10(5):359-68.AN

Abstract

Antisense oligonucleotides are currently being investigated for the treatment of a variety of diseases. Antisense drugs are being administered primarily by parenteral injection. To explore more convenient patient delivery methods, we have characterized the tissue kinetics and tolerability of an inhaled aerosol formulation of a phosphorothioate oligonucleotide in mice. Concentrations of oligonucleotide in bronchioalveolar lavage fluid, plasma, and tissue and immunohistochemical localization were used to assess deposition and pharmacokinetic parameters. Significant concentrations of oligonucleotide in lung, as well as systemic tissues, were measured following a pulmonary dose of 12 mg/kg. Doses as low as 1-3 mg/kg also produced significant concentrations of oligonucleotide (>50 microg oligonucleotide per gram of tissue), and these were maintained in the lung with a halflife of 20 hours or greater. Oligonucleotide was localized to bronchiolar epithelium and alveolar epithelium and endothelium. Toxicity was mild at the 12 mg/kg level and minimal to absent at doses of 3 mg/kg or below. Based on a favorable pharmacokinetic profile and a relative lack of toxicity, inhalation delivery appears to be a therapeutic option for antisense oligonucleotides.

Authors+Show Affiliations

Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11079575

Citation

Templin, M V., et al. "Pharmacokinetic and Toxicity Profile of a Phosphorothioate Oligonucleotide Following Inhalation Delivery to Lung in Mice." Antisense & Nucleic Acid Drug Development, vol. 10, no. 5, 2000, pp. 359-68.
Templin MV, Levin AA, Graham MJ, et al. Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. Antisense Nucleic Acid Drug Dev. 2000;10(5):359-68.
Templin, M. V., Levin, A. A., Graham, M. J., Aberg, P. M., Axelsson, B. I., Butler, M., Geary, R. S., & Bennett, C. F. (2000). Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. Antisense & Nucleic Acid Drug Development, 10(5), 359-68.
Templin MV, et al. Pharmacokinetic and Toxicity Profile of a Phosphorothioate Oligonucleotide Following Inhalation Delivery to Lung in Mice. Antisense Nucleic Acid Drug Dev. 2000;10(5):359-68. PubMed PMID: 11079575.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. AU - Templin,M V, AU - Levin,A A, AU - Graham,M J, AU - Aberg,P M, AU - Axelsson,B I, AU - Butler,M, AU - Geary,R S, AU - Bennett,C F, PY - 2000/11/18/pubmed PY - 2001/3/3/medline PY - 2000/11/18/entrez SP - 359 EP - 68 JF - Antisense & nucleic acid drug development JO - Antisense Nucleic Acid Drug Dev VL - 10 IS - 5 N2 - Antisense oligonucleotides are currently being investigated for the treatment of a variety of diseases. Antisense drugs are being administered primarily by parenteral injection. To explore more convenient patient delivery methods, we have characterized the tissue kinetics and tolerability of an inhaled aerosol formulation of a phosphorothioate oligonucleotide in mice. Concentrations of oligonucleotide in bronchioalveolar lavage fluid, plasma, and tissue and immunohistochemical localization were used to assess deposition and pharmacokinetic parameters. Significant concentrations of oligonucleotide in lung, as well as systemic tissues, were measured following a pulmonary dose of 12 mg/kg. Doses as low as 1-3 mg/kg also produced significant concentrations of oligonucleotide (>50 microg oligonucleotide per gram of tissue), and these were maintained in the lung with a halflife of 20 hours or greater. Oligonucleotide was localized to bronchiolar epithelium and alveolar epithelium and endothelium. Toxicity was mild at the 12 mg/kg level and minimal to absent at doses of 3 mg/kg or below. Based on a favorable pharmacokinetic profile and a relative lack of toxicity, inhalation delivery appears to be a therapeutic option for antisense oligonucleotides. SN - 1087-2906 UR - https://www.unboundmedicine.com/medline/citation/11079575/Pharmacokinetic_and_toxicity_profile_of_a_phosphorothioate_oligonucleotide_following_inhalation_delivery_to_lung_in_mice_ L2 - https://www.lens.org/lens/search/patent/list?q=citation_id:11079575 DB - PRIME DP - Unbound Medicine ER -