Hepatoselective Nitric Oxide (NO) Donors, V-PYRRO/NO and V-PROLI/NO, in Nonalcoholic Fatty Liver Disease: A Comparison of Antisteatotic Effects with the Biotransformation and Pharmacokinetics

Abstract

V-PYRRO/NO [O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate] and V-PROLI/NO (O2-vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate), two structurally similar diazeniumdiolate derivatives, were designed as liver-selective prodrugs that are metabolized by cytochrome P450 isoenzymes, with subsequent release of nitric oxide (NO). Yet, their efficacy in the treatment of nonalcoholic fatty liver disease (NAFLD) and their comparative pharmacokinetic and metabolic profiles have not been characterized. The aim of the present work was to compare the effects of V-PYRRO/NO and V-PROLI/NO on liver steatosis, glucose tolerance, and liver fatty acid composition in C57BL/6J mice fed a high-fat diet, as well as to comprehensively characterize the ADME (absorption, distribution, metabolism and excretion) profiles of both NO donors. Despite their similar structure, V-PYRRO/NO and V-PROLI/NO showed differences in pharmacological efficacy in the murine model of NAFLD. V-PYRRO/NO, but not V-PROLI/NO, attenuated liver steatosis, improved glucose tolerance, and favorably modified fatty acid composition in the liver. Both compounds were characterized by rapid absorption following i.p. administration, rapid elimination from the body, and incomplete bioavailability. However, V-PYRRO/NO was eliminated mainly by the liver, whereas V-PROLI/NO was excreted mostly in unchanged form by the kidney. V-PYRRO/NO was metabolized by CYP2E1, CYP2C9, CYP1A2, and CYP3A4, whereas V-PROLI/NO was metabolized mainly by CYP1A2. Importantly, V-PYRRO/NO was a better NO releaser in vivo and in the isolated, perfused liver than V-PROLI/NO, an effect compatible with the superior antisteatotic activity of V-PYRRO/NO. In conclusion, V-PYRRO/NO displayed a pronounced antisteatotic effect associated with liver-targeted NO release, whereas V-PROLI/NO showed low effectiveness, was not taken up by the liver, and was eliminated mostly in unchanged form by the kidney.

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

“…Accordingly, increased production or release of the vasoactive modulator nitric oxide (NO) could provide an effective novel strategy for the prevention and treatment of NAFLD [22]. Indeed, results of 2 studies have provided evidence consistent with this possibility.…”

“…In the first study, the administration of the hepato-selective NO donor compound [O(2)-vinyl-1(pyrrolidine-1-yl) diazen-1-ium-1,2-diolate], V_PYRRO/NO was shown to be protective against high fat-induced liver steatosis. It was suggested that such liver-targeted NO donors that are free of systemic hypotensive effects represent a promising therapeutic strategy for NAFLD [22].…”

l-Ornithine l-Aspartate (LOLA) as a Novel Approach for Therapy of Non-alcoholic Fatty Liver Disease

“…In addition, LOLA-derived glutamate can also be converted to glutathione, which is an important anti-oxidant for hepatocytes. In addition to direct effects of LOLA on the liver due to enhanced ammonia removal and improved anti-oxidative capacity, there might be indirect hepatoprotective effects due to partial reversal of sarcopenia [16] and due to nitric oxide (NO) formation from l -arginine, resulting in improved hepatic microcirculation [17]. These putative direct and indirect effects of LOLA have been demonstrated in pre-clinical and small clinical studies, awaiting confirmation in larger trials (Fig.…”

Hepatoprotection by L-Ornithine L-Aspartate in Non-Alcoholic Fatty Liver Disease

“…Было предположено, что изменения синусоидальной перфузии при стеатозе приводят к компрессии синусоидальных пространств и к последующим нарушениям печеночной микроциркуляции [21]. Поэтому увеличение выработки или высвобождения вазоактивного модулятора оксида азота (NO) может обеспечить новую эффективную стратегию предотвращения и лечения неалкогольной жировой болезни печени [22]. Действительно, результаты двух исследований представили доказательства, соответствующие этой возможности.…”

“…В ходе первого исследования было доказано, что применение гепатоселективного донатора NO соединения [O(2)-винил-1(пирролидин-1-ил) диазен-1-иум-1,2-диолата], V_PYRRO/NO, оказывает защитное действие в отношении стеатоза печени, индуцированного рационом с высоким содержанием жиров. Было предположено, что такие нацеленные на печень донаторы NO, не оказывающие системного гипотензивного действия, представляют перспективную терапевтическую стратегию при неалкогольной жировой болезни печени [22].…”