Pharmacokinetics and Metabolism of Lumiracoxib in Healthy Male Subjects

Mangold, James B.; Gu, Helen; Rodriguez, Lolita C.; Bonner, Johanne; Dickson, J.; Rordorf, Christiane

doi:10.1124/dmd.32.5.566

Cited by 77 publications

(67 citation statements)

References 16 publications

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“…This finding is consistent with data reported previously that lumiracoxib metabolism in man is catalyzed primarily by CYP2C9 (Mangold et al, 2004).…”

Section: Resultssupporting

confidence: 83%

“…In addition to forming thiol adducts, quinone imines are known to be capable of covalently modifying cellular proteins and have been implicated in a number of drug-related adverse effects (Guengerich and MacDonald, 2007;Tang, 2007). It should be noted that neither M1 nor M2 (nor other thioether conjugates) was detected in a single-dose study of lumiracoxib metabolism in four healthy male subjects (Mangold et al, 2004). However, in light of the recent withdrawal of lumiracoxib from the Australian market and its restricted use in New Zealand, further studies of the metabolic fate of the drug in humans may be warranted to better understand the relationship between lumiracoxib metabolism and its adverse hepatic effects.…”

Section: Resultsmentioning

confidence: 99%

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In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

Li¹,

Slatter²,

Zhang³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Recent clinical reports have suggested that the cyclooxygenase-2 inhibitor, lumiracoxib (Prexige), may cause a rare but serious hepatotoxicity in patients. In view of the close structural resemblance between lumiracoxib and diclofenac, a widely used nonsteroidal anti-inflammatory drug whose use also has been associated with rare cases of liver injury, it is possible that the toxicity of the two agents may share a common mechanism. Because it is believed that chemically reactive metabolites may play a role as mediators of diclofenac-mediated hepatotoxicity, the present in vitro study was carried out to test the hypothesis that lumiracoxib also undergoes metabolic activation when incubated with liver microsomal preparations and hepatocytes from rats and humans. By means of liquid chromatography tandem mass spectrometry and nuclear magnetic resonance spectrometry techniques, two previously unknown N-acetylcysteine (NAC) conjugates were identified, namely, 3-NAC-4-hydroxy lumiracoxib (M1) and 4-hydroxy-6-NAC-desfluoro lumiracoxib (M2), the structures of which reveal the intermediacy of an electrophilic quinone imine species. Based on the results of studies with immunoinhibitory antibodies, it was demonstrated that the formation of M1 and M2 in human liver microsomes was catalyzed by cytochrome P450 (P450) 2C9. These findings demonstrate that lumiracoxib is subject to P450-mediated bioactivation in both rat and human liver preparations, leading to the formation of a reactive intermediate analogous to species generated during the metabolism of diclofenac.

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“…This finding is consistent with data reported previously that lumiracoxib metabolism in man is catalyzed primarily by CYP2C9 (Mangold et al, 2004).…”

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

Li¹,

Slatter²,

Zhang³

et al. 2007

Drug Metab Dispos

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“…Indeed, the antipyretic actions of lumiracoxib and celecoxib in our model correlate well with their selectivity in inhibiting COX-2 activity. Lumiracoxib is a highly selective COX-2 inhibitor that shows potent anti-inflammatory activity (8) and differs from currently available selective COX-2 inhibitors, including celecoxib (28), in a number of important structural aspects. In our experimental paradigm, lumiracoxib proved to be a more potent antipyretic than celecoxib on fever induced by LPS or ET-1, which reflects different selectivity of the two drugs in inhibiting COX-2 in vitro: IC 50 ratio COX-1/COX-2 of 400 for lumiracoxib compared with an IC 50 ratio COX-1/COX-2 of 30 for celecoxib (8).…”

Section: Discussionmentioning

confidence: 99%

The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats

Fabricio

Veiga²,

Cristofoletti³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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It was previously shown that sustained fever can be induced in rats by central injection of endothelin-1 (ET-1). This peptide appears to participate in the mechanism(s) of LPS-induced fever, which is reduced by pretreatments with ET B receptor antagonists. In this study, we compared the effects of a nonselective cyclooxygenase (COX) inhibitor, indomethacin, with those of two selective COX-2 inhibitors, celecoxib and lumiracoxib, on ET-1-induced fever in rats. Fever induced in conscious animals by ET-1 (1 pmol icv) or LPS (5 g/kg iv) was prevented by pretreatments with celecoxib (5 and 10 mg/kg) or lumiracoxib (5 mg/kg) given by oral gavage 1 h before stimuli. Lower doses of celecoxib had partial (2.5 mg/kg) or no effect (1 mg/kg). Indomethacin (2 mg/kg ip) partially inhibited fever induced by LPS but had no effect on ET-1-induced fever. The levels of PGE2 and PGF2␣ in the cerebrospinal fluid (CSF) of pentobarbital sodium-anesthetized rats were significantly increased 3 h after the injection of LPS or ET-1. The latter increase was abolished by celecoxib at all tested doses and by indomethacin. In conclusion, selective COX-2 inhibitors were able to prevent ET-1-induced fever, indicating a role for COX-2 in this phenomenon. However, the fact that reduced CSF PG levels obtained with indomethacin and a low dose of celecoxib are not accompanied by changes in fever induced by ET-1, along with the lack of inhibitory effects of indomethacin on ET-1 fever, suggests that the latter might also involve COX-2-independent mechanisms.cyclooxygenase-2 inhibitors; indomethacin; prostaglandins; cerebrospinal fluid; lipopolysaccharide IT IS NOW WELL ESTABLISHED that the PGs represent the final mediators of fever induced by exogenous and endogenous pyrogens through an action on PG receptor-expressing neurons in the preoptic area (POA) of the anterior hypothalamus (33). In fact, PGE 2 induces fever when injected centrally (13,33,38), and its levels in the cerebrospinal fluid (CSF) and in the POA rise in parallel with the generation of fever caused by several stimuli (9,12,16,19,23,27,35,42). Moreover, the inhibition of PG synthesis by cyclooxygenase (COX) inhibitors attenuates fever in humans and experimental animals, whereas these drugs do not affect fever induced by the administration of PGs (4,7,12,13,37,39). PGF 2␣ also induces fever when injected centrally (13, 34), and its levels are increased in rat CSF in response to LPS (10).We have previously observed that endothelin-1 (ET-1), a member of the ET family of peptides (29), acts as a mediator of LPS-induced fever (15). In fact, intracerebroventricular (icv) pretreatment with the selective ET B receptor antagonist BQ-788 blunted fever induced by intravenous LPS or intracerebroventricular ET-1 (15). The rise in core temperature induced by intracerebroventricular ET-1 was accompanied by such thermoeffector response as cutaneous vasoconstriction, measured as a decrease in tail skin temperature (Fabricio, unpublished observation). The simultaneous occurrence of increased core temper...

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“…It is distinct from other COX-2 selective inhibitors in that it lacks a sulphurcontaining moiety, but rather possesses a carboxylic acid group that confers weakly acidic properties. 17 Lumiracoxib demonstrates good oral bioavailability, rapid absorption (T max 2 -3 h) with a short plasma half-life (3 -6 h), and dose-proportional, timeindependent pharmacokinetics without accumulation. 18 -21 Selectivity for COX-2 is maintained at lumiracoxib doses up to 800 mg daily.…”

Section: Efficacy Of Lumiracoxib In Osteoarthritismentioning

confidence: 99%

Efficacy of Lumiracoxib in Osteoarthritis: A Review of Nine Studies

et al. 2005

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Lumiracoxib is a cyclooxygenase-2 selective inhibitor in development for the treatment of osteoarthritis (OA), rheumatoid arthritis and acute pain. We reviewed nine clinical studies of 1 − 52 weeks' duration demonstrating the efficacy of lumiracoxib in OA. Male and female patients aged ≥ 18 years with primary OA of the hand, hip or knee received lumiracoxib, placebo or active comparators (diclofenac, celecoxib or rofecoxib). Lumiracoxib provided consistent reductions in OA pain intensity and improvements in the patient's global assessment of disease activity and functional status (assessed using the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire or the Australian/Canadian OA Hand Index). These results were superior to placebo and similar to the active comparators tested. In addition, lumiracoxib was consistently superior to placebo and generally similar to active comparators in terms of the new Outcome Measures in Clinical Trials and Osteoarthritis Research Society International criteria. These were used to provide a single measure of response to treatment, taking into account pain, the patient's global assessment of disease activity and functional status.

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Pharmacokinetics and Metabolism of Lumiracoxib in Healthy Male Subjects

Cited by 77 publications

References 16 publications

In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

In Vitro Metabolic Activation of Lumiracoxib in Rat and Human Liver Preparations

The effects of selective and nonselective cyclooxygenase inhibitors on endothelin-1-induced fever in rats

Efficacy of Lumiracoxib in Osteoarthritis: A Review of Nine Studies

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