ETODOLAC SELECTIVELY INHIBITS HUMAN PROSTAGLANDIN-G H-SYNTHASE-2 (PGHS-2) VERSUS HUMAN PGHS-1/

The isozymes of prostaglandin G/H synthase (PGHS) are shown to be diff erentially inhibited in vitro by currently marketed nonsteroidal anti- inflammatory drugs (NSAIDs) using microsomal rhPGHS-1 and rhPGHS-2. Co mparison of selectivity ratios (IC50 rhPGHS-1/IC50 rhPGHS-2) demonstra ted a 10-fold selectivity of etodolac (Lodine) for rhPGHS-2, whereas t he other NSAIDs evaluated demonstrated no preference or a slight prefe rence for inhibition of rhPGHS-1. In vitro enzyme results were support ed by a human whale blood assay where etodolac also demonstrated a 10- fold selectivity for inhibition of PGHS-2 mediated TxB(2) production. Taken together, these data may be key to explaining the clinically obs erved gastrointestinal safety of etodolac versus other marketed NSAIDs .