RESUMO
In this study, we tested whether the extent of drug presence in the heart contributes to the elevated cardiovascular risk of nonsteroidal anti-inflammatory drugs (NSAIDs). A fluorescently tagged nanoformulation of an NSAID with high cardiovascular (CV) risk (diclofenac) was developed as diclofenac ethyl ester (DFEE) encapsulated in traceable (cyanine-5.5-labeled) polymeric micelles (DFEE-TM) based on methoxypoly(ethylene oxide)-block-poly(ε-caprolactone)(PEO-b-PCL) (MW, 5000:3500 g/mol). Diclofenac pharmacokinetics and tissue distribution, as well as ex vivo near-infrared images of organs and whole bodies, were compared between healthy rats and rats with adjuvant arthritis (AA) following the administration of a single intravenous (iv) dose of DFEE-TM. Moreover, the biodistribution and antiarthritic activity of DFEE-TM were compared with those of free diclofenac (once-daily intraperitoneal, ip, 10 mg/kg for 7 days). The concentration ratios of cytochrome-P450-mediated cardiotoxic (20-hydroxyeicosatetraenoic acid) over cardioprotective (epoxyeicosatrienoic acids) metabolites of arachidonic acid (ArA) in the heart, kidneys, and plasma were measured as markers of cardiotoxicity. The nanocarrier was found in the joints of AA, but not in those of healthy rats. Both free diclofenac and DFEE-TM comparably controlled AA. Diclofenac delivery via PEO-b-PCL micelles reduced the accumulation of diclofenac in the heart of AA rats. Despite similar antiarthritic activity, the polymeric micellar formulation showed a reduction in the ratio of cardiotoxic-over-cardioprotective eicosanoids of ArA in the heart and plasma of AA rats. The results showed the positive effect of diclofenac prodrug nanodelivery in changing the normal biodistribution of diclofenac away from the heart, leading to lowered diclofenac-induced biomarkers of cardiotoxicity in the heart and plasma of AA rats.
Assuntos
Ácido Araquidônico/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/efeitos adversos , Diclofenaco/farmacologia , Coração/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Caproatos/química , Portadores de Fármacos/química , Ácidos Hidroxieicosatetraenoicos/química , Lactonas/química , Masculino , Micelas , Nanopartículas/química , Poliésteres/química , Polímeros/química , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammatory conditions such as arthritis. However, both arthritis and many NSAIDs increase cardiovascular (CV) risks. The dose-dependency of the elevated CV risks of NSAIDs has not been well-studied. We tested the hypothesis that low but still effective doses of these drugs are void of CV side effects. As the model drug, we chose diclofenac because of its known high CV toxicity, as markers of CV risks, we assessed concentrations of cytochrome P450-mediated metabolites of arachidonic acid (ArA), and we used adjuvant arthritis as an experimental model of arthritis. Following 7 daily doses (2.5-15 mg/kg), the effective dosage range of diclofenac was identified (> 5 mg/kg/day). While 7 consecutive days of low therapeutic doses did not alter the CYP-mediated ArA metabolism, the highest dose of 15 mg/kg/day caused imbalances in ArA metabolic profiles toward cardiotoxicity by increasing the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids. This is suggestive of dose-dependency of NSAID cardiotoxicity, and that low therapeutic doses may be void of CV side effects. Human studies are needed to examine the safety of low but effective doses of NSAIDs.