Lumiracoxib metabolism in male C57bl/6J mice: characterisation of novel <i>in vivo</i> metabolites

<p>1. The pharmacokinetics and metabolism of lumiracoxib in male C57bl/6J mice were investigated following a single oral dose of 10 mg/kg.</p> <p>2. Lumiracoxib achieved peak observed concentrations in the blood of 1.26 + 0.51 μg/mL 0.5 h (0.5–1.0) post-dose with an AUC_inf of 3.48 + 1.09 μg h/mL. Concentrations of lumiracoxib then declined with a terminal half-life of 1.54 + 0.31 h.</p> <p>3. Metabolic profiling showed only the presence of unchanged lumiracoxib in blood by 24 h, while urine, bile and faecal extracts contained, in addition to the unchanged parent drug, large amounts of hydroxylated and conjugated metabolites.</p> <p>4. No evidence was obtained in the mouse for the production of the downstream products of glutathione conjugation such as mercapturates, suggesting that the metabolism of the drug via quinone–imine generating pathways is not a major route of biotransformation in this species. Acyl glucuronidation appeared absent or a very minor route.</p> <p>5. While there was significant overlap with reported human metabolites, a number of unique mouse metabolites were detected, particularly taurine conjugates of lumiracoxib and its oxidative metabolites.</p

Efficacious Inhaled PDE4 Inhibitors with Low Emetic Potential and Long Duration of Action for the Treatment of COPD

Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential