Safety and pharmacokinetics of naringenin: A randomized, controlled, single‐ascending‐dose clinical trial

Abstract

Aims To evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole‐orange (Citrus sinensis) extract. Methods and methods In a single‐ascending‐dose randomized crossover trial, 18 adults ingested doses of 150 mg (NAR150), 300 mg (NAR300), 600 mg (NAR600) and 900 mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash‐out period of at least 1 week. Blood safety markers were evaluated pre‐dose and 24 hours post‐dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150 and NAR600. Four‐ and 24‐hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed‐effects linear model. Results There were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76 ± 7.88 μM (NAR150) and 48.45 ± 7.88 μM (NAR600); time to peak: 3.17 ± 0.74 hours (NAR150) and 2.41 ± 0.74 hours (NAR600); area under the 24‐hour concentration–time curve: 67.61 ± 24.36 μM × h (NAR150) and 199.05 ± 24.36 μM × h (NAR600); and apparent oral clearance: 10.21 ± 2.34 L/h (NAR150) and 13.70 ± 2.34 L/h (NAR600). Naringenin half‐life was 3.0 hours (NAR150) and 2.65 hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67 ± 5.74 μM (4 hours) and 0.35 ± 0.30 μM (24 hours). After NAR900 ingestion, serum concentrations were 43.11 ± 5.26 μM (4 hours) and 0.24 ± 0.30 μM (24 hours). Conclusions Ingestion of 150 to 900 mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 μM) is effective in primary human adipocytes, ingestion of 300 mg naringenin twice/d will likely elicit a physiological effect.

Beneficial Effects of Citrus-Derived Polymethoxylated Flavones for Central Nervous System Disorders

“…PMFs are generally quite safe, which is a major advantage. It has been shown that chronic administration of the extract of Citrus reticulata Blanco , Citrus reticulata or Citrus sinensis , which contain high concentrations of PMFs, have no harmful effects on animals [ 168 , 169 ], and humans [ 170 , 171 ].…”

Re-appraising the potential of naringin for natural, novel orthopedic biotherapies

“…In a single ascending-dose randomized controlled trial of 18 adults by Rebello et al , no adverse effects or changes in blood safety biomarkers were observed after oral consumption of 150–900 mg naringenin, the flavonone form of naringin, relative to placebo. 117 Measured serum biomarkers included alanine aminotransferase, creatinine phosphokinase, and potassium, as well as total white blood cell and eosinophil counts as markers of immune system activation. At these doses, naringin metabolites freely circulate and are effectively cleared from the body within 24 h of ingestion.…”

Naringenin Increases Insulin Sensitivity and Metabolic Rate: A Case Study

“…The quantification of naringenin in the extract, and the safety and pharmacokinetics of the extract in humans are previously described. 15 The extract contained 28% naringenin. Therefore, each capsule prepared by the PBRC pharmacist contained 536 mg of the extract.…”

“…14 We have previously shown that an aqueous and ethanolic extract of whole sweet oranges (Citrus sinensis) containing naringenin, the free aglycone form, can be readily absorbed from the small intestine and is present in human serum at concentrations sufficient to elicit a physiologic response. 15 We hypothesized that naringenin supplementation for 8 weeks would increase resting metabolic rate (RMR) and insulin sensitivity in humans. We also explored the mechanisms by which naringenin mediates thermogenesis and glucose metabolism in differentiated human adiposederived stem cells (hADSCs).…”