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Drug Metabolism and Disposition Fast Forward
First published on August 25, 2008; DOI: 10.1124/dmd.108.023150

0090-9556/08/3611-2324-2330$20.00
DMD 36:2324-2330, 2008

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Intravenous Formulation of N-Hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) for Inhibition of Rat Brain 20-Hydroxyeicosatetraenoic Acid Formation

Ying Mu, Megan M. Klamerus, Tricia M. Miller, Lisa C. Rohan, Steven H. Graham, and Samuel M. Poloyac

Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania (S.M.P., T.M.M., M.M.K., Y.M., L.C.R.); Magee-Womens Research Institute, Pittsburgh, Pennsylvania (L.C.R.); Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (S.H.G.); and Geriatric Research Educational and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (S.H.G.)

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-β-cyclodextrin results in increased aqueous solubility of HET0016 from 34.2 ± 31.2 to 452.7 ± 63.3 µg/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.

Address correspondence to: Dr. Samuel M. Poloyac, 807 Salk Hall, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261. E-mail: poloyac{at}pitt.edu






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