Metabolism and biological production of resolvins derived from docosapentaenoic acid (DPAn-6).
17S-HDPAn-6 (17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E-pentaenoic acid) and 10S,17S-HDPAn-6 (10S,17S-dihydroxydocosa-4Z,7Z,11E,13Z,15E-pentaenoic acid) are potent anti-inflammatory resolvins derived from DPAn-6 (docosapentaenoic acid n-6) and are analogous in structure and action to DHA (docosahexaenoic acid)-derived resolvins. These resolvins have proven to be potential drug candidates, albeit with therapeutic profiles that need optimization. The main objectives of this study were to evaluate key features of DPAn-6 derived resolvins that are important for therapeutic efficacy, demonstrate that these DPAn-6 resolvins could be produced naturally, and could therefore have physiological significance. Here we demonstrate biological production, examine pharmacokinetic profiles and identify key routes of metabolic inactivation of DPAn-6 derived resolvins. We compare their metabolic stability to a known resolvin, 17S-HDHA (17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid) and show that order of their stabilities is 10S,17S-HDPAn-6>17S-HDPAn-6>17S-HDHA. We show that both these compounds are not strong inhibitors of cytochrome-P450 enzymes. We evaluate activity of compounds in the delayed-type hypersensitivity model, results of which show that compounds need optimization for enhanced duration and magnitude of action. Analysis of the metabolic stability and identification of metabolites of these compounds could play an important role in the design of better analogs with longer durations of action and hence better efficacy.
Dangi
Bindi
B
Martek Biosciences Corp., 6480 Dobbin Road, Columbia, MD 21045, USA. bdangi@martek.com
Obeng
Marcus
M
Nauroth
Julie M
JM
Chung
Gloria
G
Bailey-Hall
Eileen
E
Hallenbeck
Todd
T
Arterburn
Linda M
LM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000493:pharmacokinetics; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
D000893:Anti-Inflammatory Agents; D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids; C026219:docosapentaenoic acid