Lumiracoxib

Lumiracoxib is a novel, selective COX-2 inhibitor with IC50 and K_i of 0.14 μM and 0.06 μM, exhibits 515-fold selectivity over COX-1. Phase 4.

Lumiracoxib metabolism in male C57bl/6J mice: characterisation of novel in vivo metabolites.[Pubmed:27430634]

Xenobiotica. 2017 Jun;47(6):538-546.

1. The pharmacokinetics and metabolism of Lumiracoxib in male C57bl/6J mice were investigated following a single oral dose of 10 mg/kg. 2. Lumiracoxib achieved peak observed concentrations in the blood of 1.26 + 0.51 mug/mL 0.5 h (0.5-1.0) post-dose with an AUCinf of 3.48 + 1.09 mug h/mL. Concentrations of Lumiracoxib then declined with a terminal half-life of 1.54 + 0.31 h. 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. 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. 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.

Effect of selective cyclooxygenase-2 inhibitor lumiracoxib on phenolsulfonphthalein disposition in rats.[Pubmed:24870608]

Drug Metabol Drug Interact. 2014;29(3):203-6.

Selective cyclooxygenase-2 inhibitor Lumiracoxib was shown to have the strong inhibitory potencies on the renal organic anion transporter (OAT)1 and also on OAT3 from drug transport experiments. The purpose of this study was to examine the effect of Lumiracoxib on disposition of phenolsulfonphthalein (PSP) - which is mainly excreted into urine via OATs - from in vivo experiments. After the intravenous injection of PSP and Lumiracoxib into rats, pharmacokinetic analysis was performed. After the intravenous injection of PSP as a bolus, its plasma concentration decreased time-dependently. Until 60 min after the injection, 51.1% of the dose was recovered into urine. The simultaneous administration of Lumiracoxib increased the plasma levels of PSP and reduced its urinary recovery to 23.6% of the dose. The pharmacokinetic analysis using a two-compartment model exhibited that Lumiracoxib affected the parameters implying the elimination of PSP. The present study demonstrates that Lumiracoxib interfered with urinary excretion of PSP in rats.

The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.[Pubmed:28351678]

Biochem Pharmacol. 2017 Jul 1;135:139-150.

The pharmacokinetics and metabolism of Lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, Lumiracoxib reached peak observed concentrations in the blood of 1.10+/-0.08mug/mL at 0.25-0.5h post-dose with an AUCinf of 1.74+/-0.52mugh/mL and an effective half-life for the drug of 1.42+/-0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15+/-0.08mug/mL at 0.25h post-dose with an AUCinf of 1.94+/-0.22mugh/mL and an effective half-life of 1.28+/-0.02h (n=3). Analysis of blood indicated only the presence of unchanged Lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans.

Similar maximum systemic but not local cyclooxygenase-2 inhibition by 50 mg lumiracoxib and 90 mg etoricoxib: a randomized controlled trial in healthy subjects.[Pubmed:24469906]

Pharm Res. 2014 Jul;31(7):1813-22.

PURPOSE: Once daily doses of 100-400 mg Lumiracoxib have been proposed to inhibit local prostaglandin synthesis longer than systemic prostaglandin synthesis due to local accumulation in inflamed, acidic tissue. Lower, less toxic doses, however, might still achieve the clinical goal and merit further contemplation. METHODS: In a randomized, double-blind, placebo-controlled, three-way cross-over study, 18 healthy men received, with an interval of 24 h, two oral doses of 50 mg Lumiracoxib or for comparison, 90 mg etoricoxib, for which local tissue accumulation has not been claimed as therapeutic component. Systemic and local drug concentrations, assessed by means of subcutaneous in-vivo microdialysis, were related to COX-2 inhibiting effects, quantified as inhibition of prostaglandin ex-vivo production in whole blood as well as local tissue prostaglandin (PG) concentrations. RESULTS: Twenty-four hours after the first dose, only etoricoxib was detectable in plasma and inhibited PGE2 production. In contrast, after the second dose, systemic PGE2 concentrations were significantly reduced by both coxibs, indicating similar maximum systemic effects of the selected doses. The local COX-2 inhibition by etoricoxib was most pronounced for PGD2. To the contrary, no indication was given of local inhibition of PG production by Lumiracoxib at the dose tested. CONCLUSIONS: Doses of 50 mg Lumiracoxib and 90 mg etoricoxib produced similar maximum inhibition of systemic COX-2 function whereas 50 mg Lumiracoxib was ineffective in producing local COX-2 inhibition. At a 50 mg dosage, Lumiracoxib does not provide peripheral effects that outlast its systemic actions in therapies of rheumatic diseases such as osteoarthritis.