Metabolism and excretion studies of oral administered naringin, a putative antitussive, in rats and dogs

Abstract

Naringin, a major active flavonone glycoside from a traditional Chinese medicine Huajuhong, has been demonstrated to have activities such as peripheral antitussive, mucoregulator and anti-inflammatory. The purpose of this study was to elucidate the metabolism and mass balance of orally administered naringin in rats and dogs. After oral administration of naringin to rats and dogs at doses of 42 mg/kg and 12.4 mg/kg, respectively, metabolites in excreta were identified using a LC-Q-TOF system. The major metabolites including naringin, total naringenin (including free naringenin and its conjugates) and 4-hydroxyphenylpropionic acid in excreta were quantified by a LC-MS/MS system. Twenty-two metabolites were identified in dogs and 17 metabolites were detected in rats. The observed routes of naringin metabolism were hydroxylation, methylation, acetylation, hydrogenation, deglycosylation, dehydrogenation, glucuronidation, sulfation, glucosylation, ring-fission, oxidation, glycine conjugation and dehydroxylation. On the basis of these identified metabolites, a comprehensive metabolic pathway of naringin was proposed. About 21% of administered naringin was recovered in rat excreta in the form of naringin, total naringenin and 4-hydroxyphenylpropionic acid, and about 60% was recovered in dog excreta. The levels of 4-hydroxyphenylpropionic acid in excreta were higher than those of naringin and total naringenin, and the quantified metabolites were excreted more through feces, rather than urine. Most of these metabolites were excreted within 36 h post dose. The results of metabolism and excretion studies provide an explanation for future pharmacological and toxicological findings and are the groundwork for clinical studies.

Therapeutic effects of naringin in a guinea pig model of ovalbumin-induced cough-variant asthma

“…In pharmacokinetic studies, naringin was administered orally to rats at a dose of 42 mg/kg, which was converted from 36.8 mg/kg in guinea pigs [23,24]. Thus, the middle dose (18.4 mg/kg) was chosen in the present study based on pharmacodynamic and pharmacokinetic studies.…”

Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species

“…Subsequently, the metabolites are transported, mainly via the portal vein, to the liver for further biotransformation to glucuronide and sulphate conjugates, which enter systemic circulation (Tsai and Tsai, 2012). Finally, naringin, naringenin, and their conjugates are secreted into bile and excreted into the feces or reabsorbed to become systemically available (i.e., through enterohepatic circulation) (Ma et al, 2006;Liu M. et al, 2012;Zeng et al, 2017). Since the glucuronide and sulphate conjugates of flavonoids were reported as precursors of bioactive metabolites (glycoside or aglycone) (Terao et al, 2011;Matsumoto et al, 2018), hydrolysis with b-glucuronidase is often used in pharmacokinetic studies of naringin or naringenin.…”

Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway

“…The flavonoid naringin (NAR; 4' ,5,7-trihydroxyflavanone-7-rhamnoglucoside) is a polyphenolic compound that naturally occurs in citrus fruit. NAR has previously been shown to have anti-inflammatory (17,18), antioxidant (19,20), anticancer (21), antibacterial (22), antimutagenic (23), antiulcer, antitussive (24,25), neuroprotective (26)(27)(28), as well as antihypertensive properties (29), and can reduce blood cholesterol levels, preventing thrombosis (30). In recent years, it has been reported that NAR inhibits the apoptosis of hydrogen peroxide-induced p388 cells (31) and Rotenone-induced human neuroblastoma SH-SY5Y cells (32).…”