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

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 the complex as a single HET0016 i.v. dose (1 mg/kg) rapidly reduced rat brain 20-HETE concentrations from 289 to 91 pmol/g. Collectively, these data demonstrate that the i.v. formulation of HET0016 rapidly penetrates the rat brain and significantly inhibits 20-HETE tissue concentrations. These results will enable future studies to determine biopharmaceutics of HET0016 for inhibition of 20-HETE after cerebral ischemia.
AuthorsYing Mu, Megan M Klamerus, Tricia M Miller, Lisa C Rohan, Steven H Graham, Samuel M Poloyac
JournalDrug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 36 Issue 11 Pg. 2324-30 (Nov 2008) ISSN: 1521-009X [Electronic] United States
PMID18725506 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Amidines
  • Cytochrome P-450 Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Amidines (administration & dosage, chemistry)
  • Animals
  • Brain (drug effects, enzymology, metabolism)
  • Chemistry, Pharmaceutical
  • Cytochrome P-450 Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, metabolism)
  • Injections, Intravenous
  • Male
  • Rats
  • Rats, Sprague-Dawley

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: