Aging is an inevitable biological process characterized by the loss of functional capacity and associated with changes in all phases of pharmacokinetic processes. Naringin, a dietary flavanone glycoside, has been proved to be beneficial for the treatment of multiple age-associated chronic diseases. To date, the pharmacokinetic processes of naringin in aged individuals are still unknown. Thus, a rapid resolution liquid chromatography tandem triple quadrupole mass spectrometry (RRLC-QQQ-MS/MS) method was established for the determination of naringin and its metabolite naringenin in rat plasma, urine, feces, and tissue homogenate. The pharmacokinetic parameters were calculated and a higher exposure of naringin and naringenin were observed in aged rats. Naringin and naringenin were mostly distributed in gastrointestinal tract, liver, kidney, lung, and trachea. Furthermore, a total of 39 flavonoid metabolites (mainly glucuronides and sulfates) and 46 microbial-derived phenolic catabolites were screened with ultra-fast liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS). Naringenin, hippuric acid, and 3-(4’-hydroxyphenyl)propionic acid were predominated metabolites. This study systemically investigated the pharmacokinetics, tissue distribution, metabolism, and excretion of naringin in aged rats, revealing age- and gender-related changes in the in vivo behavior of naringin. These results would be helpful for the interpretation of pharmacokinetics and pharmacodynamics of naringin in aged population.

Background: Pharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development. Methods: Separate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry. Results: The pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin. Conclusion: The results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/eap/main, identifiers CTR20130704 and CTR20190127.

Exocarpium Citri grandis (ECG) is an important Traditional Chinese Medicine (TCM) for the treatment of cough and phlegm, and the flavonoids contained were considered the main effective components. To date, the systematic chemical profiling of these flavonoids and derived in vivo metabolites in human have not been well investigated. ECG was extracted using boiling water and then provided to volunteers for oral administration. Following the ingestion, urine samples were collected from volunteers over 48 h. The extract and urine samples were analyzed using ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS) system to screen and identify flavonoids and derived in vivo metabolites. A total of 18 flavonoids were identified in the ECG extract, and 20 metabolites, mainly glucuronide and sulfate conjugates, were screened in urine samples collected post consumption. The overall excretion of naringenin metabolites corresponded to 5.45% of intake and occurred mainly within 4–12 h after the ingestion. Meanwhile, another 29 phenolic catabolites were detected in urine. Obtained data revealed that flavonoids were abundant in the ECG extract, and these components underwent extensive phase II metabolism in humans. These results provided valuable information for further study of the pharmacology and mechanism of action of ECG.

Citri reticulatae pericarpium (CRP), the dried pericarps of Citrus reticulata Blanco and its cultivars, has been widely used in drugs and foods in China for centuries. In this study, an accurate and feasible analytical method based on HS-SPME-GC-MS coupled with multivariate statistical analyses was developed to comprehensively compare volatile compounds of pericarps derived from Citrus reticulata “Chachi” (“Guangchenpi” in Chinese, GCP) and other cultivars of Citrus reticulata Blanco (“Chenpi” in Chinese, CP). Principal component analysis, hierarchical cluster analysis, and orthogonal partial least-squares-discrimination analysis were performed to extract meaningful attributes from volatile profiles based on GC-MS data. Results indicated that samples from GCP and CP could easily be differentiated, and seven potential chemical markers were screened for the quality control of CRP. This study illuminated the volatile profile in CRP, and provides a practical method for the authentication of CRP varieties.