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In Vitro Metabolism of 2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] Acetic Acid (Licofelone, ML3000), an Inhibitor of Cyclooxygenase-1 and -2 and 5-Lipoxygenase

c-a-i-r biosciences GmbH, Tuebingen, Germany (W.A., A.U.); University of Tuebingen, Institute of Pharmacy, Tuebingen, Germany (S.L.); Department of General, Visceral and Transplantation Surgery, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany (A.K.N.); and Merckle GmbH, Department of Drug Research, Ulm, Germany (W.A.)

2-[6-(4-Chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid (licofelone) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase and under development for treatment of osteoarthritis. In conventional in vitro assays using liver microsomes and NADPH as cosubstrate, a high metabolic stability of licofelone was observed. In the presence of UDP-glucuronic acid, licofelone is rapidly converted into the corresponding acyl glucuronide, M1. These results are in conflict with data from clinical studies. After administration of licofelone to humans, M1 plasma concentrations were negligibly low, whereas the exposure of the hydroxy-metabolite M2 achieved values of approximately 20% compared with that of the parent drug. Metabolism studies with human hepatocytes and dual-activity assays with microsomes, which allowed the simultaneous monitoring of hydroxylation and glucuronidation reactions, were performed, and the metabolic pathway of licofelone was elucidated. After glucuronidation, predominantly catalyzed by UDP glucuronosyltransferase (UGT) isoforms UGT2B7, UGT1A9, and UGT1A3, M1 is converted into the hydroxy-glucuronide M3 in a CYP2C8-dependent reaction. The enzyme specificities were investigated using recombinant human cytochrome P450 and UGT isoforms as test systems. In vitro drug-interaction studies using the 6-hydroxylation of paclitaxel as control reaction confirmed that neither licofelone nor M1 is a relevant inhibitor of CYP2C8. The formation of M3 was also observed with liver microsomes from cynomolgus monkeys, but in incubations with mouse and rat liver microsomes, M1 remained unchanged. The clinical relevance of these findings is discussed.