Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats

Florian Eyer, Werner Steimer, Thomas Nitzsche, Nicole Jung, Heidi Neuberger, Christine Müller, Martin Schlapschy, Thomas Zilker, Arne Skerra

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

23 Zitate (Scopus)

Abstract

Lipocalins tailored with high affinity for prescribed ligands, so-called anticalins, constitute promising candidates as antidotes. Here, we present an animal study to investigate both pharmacokinetic and clinical effects of an anticalin specific for the digitalis compound digoxin. Intravenous digoxin (2.5-50. μg/kg/min) was administered to rats until first changes in the ECG occurred (dose finding study) or a priori for 30. min (kinetic study). The anticalin DigA16(H86N), dubbed DigiCal, was administered intravenously at absolute doses of 1, 5, 10 and 20. mg, while the control group received isotonic saline. Hemodynamic changes, several ECG parameters and digoxin concentration in plasma were monitored at given time intervals. After DigiCal administration free digoxin concentration in plasma ultrafiltrate declined dramatically within 1. min to the presumably non-toxic range. There was also a significant and DigiCal dose-dependent effect on longer survival, less ECG alterations, arrhythmia, and improved hemodynamics. Infusion of a lower digoxin dose (2.5. μg/kg/min) resulted in a more sustained reduction of free digoxin in plasma after DigiCal administration compared to a higher digoxin dose (25. μg/kg/min), whereas ECG and hemodynamic parameters did not markedly differ, reflecting the known relative insensitivity of rats towards digoxin toxicity. Notably, we observed a re-increase of free digoxin in plasma some time after bolus administration of DigiCal, which was presumably due to toxin redistribution from tissue in combination with the relatively fast renal clearance of the rather small protein antidote. We conclude that anticalins with appropriately engineered drug-binding activities and, possibly, prolonged plasma half-life offer prospects for next-generation antidotal therapy.

OriginalspracheEnglisch
Seiten (von - bis)352-359
Seitenumfang8
FachzeitschriftToxicology and Applied Pharmacology
Jahrgang263
Ausgabenummer3
DOIs
PublikationsstatusVeröffentlicht - 15 Sept. 2012

Fingerprint

Untersuchen Sie die Forschungsthemen von „Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats“. Zusammen bilden sie einen einzigartigen Fingerprint.

Dieses zitieren