Academic Journal
Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme
العنوان: | Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme |
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المؤلفون: | Nelissen, J., Lemkens, P., Sann, H., Bindl, M., Bassissi, F., Jasserand, D., De Mey, J. G. R., Janssen, B. J. A. |
المصدر: | Nelissen , J , Lemkens , P , Sann , H , Bindl , M , Bassissi , F , Jasserand , D , De Mey , J G R & Janssen , B J A 2012 , ' Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme ' , Life Sciences , vol. 91 , no. 13-14 , pp. 587-592 . https://doi.org/10.1016/j.lfs.2012.01.015 |
سنة النشر: | 2012 |
المجموعة: | Maastricht University Research Publications |
مصطلحات موضوعية: | Endothelin converting enzyme, Neutral endopeptidase, Calcitonin gene-related peptide, Metalloproteases, Kidney |
الوصف: | Aims: The pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined. Main methods: The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo. Key findings: In vitro, at neutral pH, 10 mu M SOL1 inhibited NEP-1. NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC(50)s were 25, 25 and 3200 nmol/L, respectively. In anesthetized rats. SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1-31) with ED(50)s of 1.9 and 0.03 mg/kg, corresponding to plasma EC(50)s of 4.6 and 0.1 mu mol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9 ml/kg.min and T-1/2 between 20 and 60 min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3 weeks at 50 mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 mu mol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 mu mol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine. Significance: These data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model. |
نوع الوثيقة: | article in journal/newspaper |
اللغة: | English |
DOI: | 10.1016/j.lfs.2012.01.015 |
الاتاحة: | https://cris.maastrichtuniversity.nl/en/publications/1d6ee986-c85e-45d4-a14d-87facbb618c4 https://doi.org/10.1016/j.lfs.2012.01.015 |
Rights: | info:eu-repo/semantics/openAccess |
رقم الانضمام: | edsbas.ED151567 |
قاعدة البيانات: | BASE |
DOI: | 10.1016/j.lfs.2012.01.015 |
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