Intravenous formulation of N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) for inhibition of rat brain 20-hydroxyeicosatetraenoic acid formation.

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Ying MuSamuel M Poloyac

Abstract

N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) is a potent inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) formation by specific cytochrome P450 isoforms. Previous studies have demonstrated that administration of HET0016 inhibits brain formation of 20-HETE and reduces brain damage in a rat model of thromboembolic stroke. Delineation of the dose, concentration, and neuroprotective effect relationship of HET0016 has been hampered by the relative insolubility of HET0016 in aqueous solutions and the lack of information concerning the mechanism and duration of HET0016 inhibition of brain 20-HETE formation. Therefore, it was the purpose of this study to develop a water-soluble formulation of HET0016 suitable for intravenous (i.v.) administration and to determine the time course and mechanism of brain 20-HETE inhibition after in vivo dosing. In this study we report that HET0016 is a noncompetitive inhibitor of rat brain 20-HETE formation, which demonstrates a tissue concentration range for brain inhibition. In addition, we demonstrate that complexation of HET0016 with hydroxypropyl-beta-cyclodextrin results in increased aqueous solubility of HET0016 from 34.2 +/- 31.2 to 452.7 +/- 63.3 microg/ml. Administration of...Continue Reading

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Citations

Jun 11, 2011·Experimental Eye Research·Zhongli WangNorman R Harris
Jun 11, 2015·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Jafar Sadik B ShaikMioara D Manole
Mar 1, 2019·Journal of Neurotrauma·Samuel M PoloyacPunit Marathe
Jul 6, 2014·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Yi ZhangMong-Heng Wang
Nov 7, 2009·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Tricia M MillerSamuel M Poloyac

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