Presystemic Metabolism of AZ’0908, A Novel mPGES-1 Inhibitor: An In Vitro and In Vivo Cross-Species Comparison

• Published in: Journal of pharmaceutical sciences Vol. 102; no. 3; pp. 1106 - 1115
• Main Authors: Bylund, Johan, Bueters, Tjerk
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.03.2013; Wiley Subscription Services, Inc., A Wiley Company; Elsevier Limited
• Subjects: ABC transporters; Animals; Benzamides - metabolism; Benzamides - pharmacokinetics; bioavailability; Biological Availability; Caco-2 Cells; CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Dogs; Female; first-pass metabolism; Humans; interspecies correlation; intestinal loss; intestinal metabolism; Intestines - metabolism; Intramolecular Oxidoreductases - antagonists & inhibitors; Intramolecular Oxidoreductases - metabolism; Liver - metabolism; Male; Metabolic Clearance Rate; Microsomes - metabolism; pharmacokinetics; Prostaglandin-E Synthases; Rats; Rats, Sprague-Dawley; Sulfonamides - metabolism; Sulfonamides - pharmacokinetics; Triazoles - pharmacology; CYP2J2; interspecies correlation; bioavailability; intestinal loss; pharmacokinetics; first-pass metabolism; ABC transporters; intestinal metabolism
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.23443

AZ’0908 is a novel microsomal prostaglandin E synthase-1 inhibitor intended for oral administration. Pharmacokinetic experiments in rats showed that bioavailability was much lower than anticipated and increased following pretreatment with the nonspecific cytochrome P450 (CYP) inhibitor 1-aminobenzotriazole, presumably by inhibition of intestinal metabolism. Stability experiments in rat liver and intestinal fractions revealed that the intrinsic clearance (Clint) was much higher in intestinal than in liver microsomes. Caco2 experiments showed that AZ’0908 was a substrate for breast cancer resistance protein. Permeability was generally high and the efflux component was saturable predicting good absorption. The Clint values in human intestinal microsome and S9 fractions were low. A correlation occurred between in vitro intestinal metabolism and in vivo intestinal loss in rats and dogs. Enzyme identification experiments showed that human CYP2J2 was involved in the oxidation of AZ’0908. In rats, the major metabolic enzyme was not identified. However, rat CYP2J2 analogs were not investigated. Intestinal metabolism appeared to be a major occurrence, explaining intestinal loss of AZ’0908 in the rats. In view of good overall permeability, low in vitro intestinal turnover, and relative low intestinal abundance of CYP2J2, we predict that intestinal metabolism of AZ’0908 in human does not exert a major issue. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1106-1115, 2013