Kus Kamil, Walczak Maria, Maslak Edyta, Zakrzewska Agnieszka, Gonciarz-Dytman Anna, Zabielski Piotr, Sitek Barbara, Wandzel Krystyna, Kij Agnieszka, Chabowski Adrian, Holland Ryan J, Saavedra Joseph E, Keefer Larry K, Chlopicki Stefan
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.).
Jagiellonian Centre for Experimental Therapeutics (K.K., M.W., E.M., A.Z., A.G.-D., B.S., K.W., A.K., S.Ch.), Department of Pharmacokinetics and Physical Pharmacy, Medical College (K.K., M.W., A.G.-D., A.K.), and Department of Experimental Pharmacology, Chair of Pharmacology, Medical College (S.Ch.), Jagiellonian University, Krakow, Poland; Department of Physiology, Medical University of Bialystok, Bialystok, Poland (P.Z., A.Ch.); Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland (J.E.S.); and Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland (R.J.H., L.K.K.)
Drug Metab Dispos. 2015 Jul;43(7):1028-36. doi: 10.1124/dmd.115.063388. Epub 2015 Apr 13.
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.
V-吡咯/NO [O(2)-乙烯基-1-(吡咯烷-1-基)重氮-1,2-二醇盐] 和V-脯氨酸/NO（O2-乙烯基-[2-(羧基)吡咯烷-1-基]重氮-1,2-二醇盐），两种结构相似的重氮二醇盐衍生物，被设计为肝脏选择性前药，可被细胞色素P450同工酶代谢，随后释放一氧化氮（NO）。然而，它们在治疗非酒精性脂肪性肝病（NAFLD）中的疗效以及它们的比较药代动力学和代谢谱尚未得到表征。本研究的目的是比较V-吡咯/NO和V-脯氨酸/NO对高脂饮食喂养的C57BL/6J小鼠肝脏脂肪变性、葡萄糖耐量和肝脏脂肪酸组成的影响，以及全面表征两种NO供体的ADME（吸收、分布、代谢和排泄）谱。尽管它们结构相似，但V-吡咯/NO和V-脯氨酸/NO在NAFLD小鼠模型中的药理疗效存在差异。V-吡咯/NO可减轻肝脏脂肪变性、改善葡萄糖耐量并有利地改变肝脏中的脂肪酸组成，而V-脯氨酸/NO则无此作用。两种化合物的特点都是腹腔注射后吸收迅速、从体内快速消除且生物利用度不完全。然而，V-吡咯/NO主要通过肝脏消除，而V-脯氨酸/NO大多以原形经肾脏排泄。V-吡咯/NO由CYP2E1、CYP2C9、CYP1A2和CYP3A4代谢，而V-脯氨酸/NO主要由CYP1A2代谢。重要的是，V-吡咯/NO在体内和离体灌注肝脏中比V-脯氨酸/NO是更好的NO释放剂，这一效应与V-吡咯/NO的优越抗脂肪变性活性相符。总之，V-吡咯/NO显示出与肝脏靶向性NO释放相关的明显抗脂肪变性作用，而V-脯氨酸/NO效果不佳，未被肝脏摄取，且大多以原形经肾脏排泄。
