Abstract
Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5. mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.
| Original language | English (US) |
|---|---|
| Journal | Prostaglandins and Other Lipid Mediators |
| DOIs | |
| State | Accepted/In press - Feb 27 2015 |
Fingerprint
Keywords
- Caco-2 intestinal absorption
- EETs
- Eicosanoids
- Epoxy fatty acids
- Oxylipins
- Primary rat hepatocytes
- Soluble epoxide hydrolase
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Pharmacology
- Cell Biology
Cite this
Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) : Resulting drug levels and modulation of oxylipin pattern. / Ostermann, Annika I.; Herbers, Jan; Willenberg, Ina; Chen, Rongjun; Hwang, Sung Hee; Greite, Robert; Morisseau, Christophe; Gueler, Faikah; Hammock, Bruce D.; Schebb, Nils Helge.
In: Prostaglandins and Other Lipid Mediators, 27.02.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU)
T2 - Resulting drug levels and modulation of oxylipin pattern
AU - Ostermann, Annika I.
AU - Herbers, Jan
AU - Willenberg, Ina
AU - Chen, Rongjun
AU - Hwang, Sung Hee
AU - Greite, Robert
AU - Morisseau, Christophe
AU - Gueler, Faikah
AU - Hammock, Bruce D.
AU - Schebb, Nils Helge
PY - 2015/2/27
Y1 - 2015/2/27
N2 - Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5. mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.
AB - Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5. mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible.
KW - Caco-2 intestinal absorption
KW - EETs
KW - Eicosanoids
KW - Epoxy fatty acids
KW - Oxylipins
KW - Primary rat hepatocytes
KW - Soluble epoxide hydrolase
UR - http://www.scopus.com/inward/record.url?scp=84937061095&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937061095&partnerID=8YFLogxK
U2 - 10.1016/j.prostaglandins.2015.06.005
DO - 10.1016/j.prostaglandins.2015.06.005
M3 - Article
C2 - 26117215
AN - SCOPUS:84949627199
JO - Prostaglandins and Other Lipid Mediators
JF - Prostaglandins and Other Lipid Mediators
SN - 1098-8823
ER -