Details

Autor(en) / Beteiligte

• Turowska, Agnieszka
• Librizzi, Damiano
• Baumgartl, Nadja
• Kuhlmann, Jens
• Dicke, Tanja
• Merkel, Olivia
• Homburg, Ursula
• Höffken, Helmut
• Renz, Harald
• Garn, Holger

Titel

Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs

Ist Teil von

• Toxicology and applied pharmacology, 2013-10, Vol.272 (2), p.365-372

Ort / Verlag

Amsterdam: Elsevier Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• The DNAzyme hgd40 was shown to effectively reduce expression of the transcription factor GATA-3 RNA which plays an important role in the regulation of Th2-mediated immune mechanisms such as in allergic bronchial asthma. However, uptake, biodistribution and pharmacokinetics of hgd40 have not been investigated yet. We examined local and systemic distribution of hgd40 in naive mice and mice suffering from experimental asthma. Furthermore, we evaluated the pharmacokinetics as a function of dose following single and repeated administration in rats and dogs. Using intranasal administration of fluorescently labeled hgd40 we demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled hgd40. After intratracheal application, highest amounts of hgd40 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic hgd40 levels were detected already at 5min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of hgd40 were detectable in lungs up to 7days p.a. Also in the toxicologically relevant rats and dogs, hgd40 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats. These pharmacokinetic of hgd40 provide guidance for clinical development, and support an infrequent and convenient dose administration regimen. •Local and systemic distribution of GATA-3-specific DNAzyme hgd40 was investigated.•Pharmacokinetics of hgd40 was tested in rats and dogs.•hgd40 dissolved in PBS was easily taken up into the lungs after local application.•No accumulation of hgd40 was observed after multiple treatments.•Pharmacokinetic properties of hgd40 support convenient dose administration regimen.