Abstract
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 6α-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.
Footnotes
-
The hepatocyte work was partially supported by the Federal Ministry of Education and Research (BMBF 0313081B).
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.020347.
-
ABBREVIATIONS: licofelone, 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid, ML3000; COX, cyclooxygenase; 5-LOX, 5-lipoxygenase; NSAID, nonsteroidal anti-inflammatory drug; P450, cytochrome P450; G6P, glucose-6-phosphate; UDPGA, UDP-glucuronic acid; UGT, UDP glucuronosyltransferase; DLM, beagle dog liver microsomes; NZLM, New Zealand White rabbit liver microsomes; HIM, human intestinal microsomes; HKM, human kidney microsomes; HLuM, human lung microsomes; HLM, human liver microsomes; CLM, cynomolgus monkey liver microsomes; RLM, Sprague-Dawley rat liver microsomes; MLM, CD-1 mouse liver microsomes; CIM, cynomolgus monkey intestinal microsomes; BSA, bovine serum albumin; ISTD, internal standard; ACN, acetonitrile; LC/MS/MS, liquid chromatography/tandem mass spectrometry; HPLC, high-performance liquid chromatography.
-
↵1 Current affiliation: Department of Traumatology, TU Munich, Munich, Germany.
- Received January 2, 2008.
- Accepted February 8, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|