期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 165, 期 5, 页码 1401-1412出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1476-5381.2011.01641.x
关键词
soluble epoxide hydrolase inhibitors; pharmacokinetics; cynomolgus monkeys; atherosclerosis
资金
- NIEHS [R01 ES002710]
- National Institute of Environmental Health Sciences [P42 ES004699]
- National Center for Research Resources [R24 RR022191]
- National Institute on Aging [R01 AG027847]
- NIH/ NHLBI [F32 HL078096]
BACKGROUND AND PURPOSE Soluble epoxide hydrolase inhibitors (sEHIs) possess anti-inflammatory, antiatherosclerotic, antihypertensive and analgesic properties. The pharmacokinetics (PK) and pharmacodynamics in terms of inhibitory potency of sEHIs were assessed in non-human primates (NHPs). Development of a sEHI for use in NHPs will facilitate investigations on the role of sEH in numerous chronic inflammatory conditions. EXPERIMENTAL APPROACH PK parameters of 11 sEHIs in cynomolgus monkeys were determined after oral dosing with 0.3 mg.kg(-1). Their physical properties and inhibitory potency in hepatic cytosol of cynomolgus monkeys were examined. Dose-dependent effects of the two inhibitors 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) and the related acetyl piperidine derivative, 1-trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea (TPAU), on natural blood eicosanoids, were determined. KEY RESULTS Among the inhibitors tested, TPPU and two 4-(cyclohexyloxy) benzoic acid urea sEHIs displayed high plasma concentrations (> 10 x IC50), when dosed orally at 0.3 mg.kg(-1). Although the 4-(cyclohexyloxy) benzoic acid ureas were more potent against monkey sEH than piperidyl ureas (TPAU and TPPU), the latter compounds showed higher plasma concentrations and more drug-like properties. The Cmax increased with dose from 0.3 to 3 mg.kg(-1) for TPPU and from 0.1 to 3 mg.kg(-1) for TPAU, although it was not linear over this range of doses. As an indication of target engagement, ratios of linoleate epoxides to diols increased with TPPU administration. CONCLUSION AND IMPLICATIONS Our data indicate that TPPU is suitable for investigating sEH biology and the role of epoxide-containing lipids in modulating inflammatory diseases in NHPs.
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