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Reduced Heart Exposure of Diclofenac by Its Polymeric Micellar Formulation Normalizes CYP-Mediated Metabolism of Arachidonic Acid Imbalance in An Adjuvant Arthritis Rat Model: Implications in Reduced Cardiovascular Side Effects of Diclofenac by Nanodrug Delivery
journal contribution
posted on 2020-02-24, 13:47 authored by Hanan Al-Lawati, Mohammad Reza Vakili, Afsaneh Lavasanifar, Surur Ahmed, Fakhreddin JamaliIn
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.
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Reduced Cardiovascular Side EffectsAA ratsplasmanonsteroidal anti-inflammatory drugsDFEEPCLaciddiclofenac ethyl esterantiarthritic activityAdjuvant Arthritis Rat ModelMWDiclofenacvivo near-infrared imagesDFEE-TMPEONSAIDCVReduced Heart Exposurediclofenac prodrug nanodeliveryPolymeric Micellar Formulation Normalizes CYP-Mediated Metabolism
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