Pharmacokinetics of the Urokinase Receptor-Derived Peptide UPARANT After Single and Multiple Doses Administration in Rat
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ORIGINAL RESEARCH ARTICLE
Pharmacokinetics of the Urokinase Receptor‑Derived Peptide UPARANT After Single and Multiple Doses Administration in Rats Michele Ciccone1 · Daniele D’Alonzo2 · Alfonsina Mariarosaria Cangiano1 · Maria De Fenza2 · Vincenzo Pavone2 · Angelo Mancinelli1
© Springer Nature Switzerland AG 2020
Abstract Background and Objectives UPARANT has emerged as a novel therapeutic agent with the potential to treat ocular diseases as assessed by studies in animal models. Since limited information is available on the pharmacokinetics of UPARANT, the aim of this study is to evaluate its pharmacokinetics after single and multiple ascending dose (SAD and MAD) administration in rats. Methods Male (n = 27) and female (n = 27) Sprague-Dawley rats were divided into six groups (n = 9/sex/group). UPARANT was administered via subcutaneous injection as single (10, 50 or 100 mg/kg; day 1) and multiple (10, 50 or 100 mg/kg/day; 7 consecutive days; day 7) dosing. Blood samples were collected on day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 h post dose) and day 7 (pre-dose, 0.5, 1, 2, 4, 8, 24, 48 and 192 h post dose). The plasma concentration of UPARANT was determined by a validated liquid chromatography mass spectrometry method. Results The plasma concentration-time profiles of UPARANT were similar in SAD and MAD administration in both male and female rats. The compound reached maximum plasma concentration (Cmax) at 1–2 h with a slow apparent plasma clearance and a moderate apparent volume of distribution. Moreover, SAD administration revealed a non-proportional increase in Cmax and in the area under the plasma concentration-time curve (AUCinf), whereas a dose-proportional increase in AUCinf was shown after MAD administration. Regarding the extent of accumulation, the data suggest negligible accumulation of the compound after multiple administrations. Conclusion The pharmacokinetics of UPARANT were not sex-related, and there was negligible accumulation in plasma after 7 days of treatment. However, the compound exhibited no dose-proportional pharmacokinetics after single and multiple ascending subcutaneous dosing.
1 Introduction Angiogenesis is a complex multistep process leading to the formation of new blood vessels from the existing vascular network. The new blood vessel formation is regulated by various factors, such as vascular endothelial growth factor (VEGF), the plasminogen-activator system and inflammatory factors. In particular, the plasminogen activation is finely controlled through two plasminogen activators (PAs), localized activation and interaction with specific inhibitors * Angelo Mancinelli [email protected] 1
MIR (Medicinal Investigational Research), Biogem Research Institute, Ariano Irpino, Italy
Department of Chemical Sciences, University of Naples “Federico II”, Naples, Italy
2
(PAIs). One of the two PAs is represented by tissue-type PA (tPA), which has a high affinity for fibrin resulting in a strong involvement in the fibrinolytic process. The other PA, the urokinase-type PA
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