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. 2019 Jan 28:10:34.
doi: 10.3389/fphar.2019.00034. eCollection 2019.

Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Naringin in Aged Rats

Xuan Zeng  1 , Weiwei Su  1 , Yuying Zheng  1 , Yudong He  1 , Yan He  1 , Hongyu Rao  1 , Wei Peng  1 , Hongliang Yao  1
Affiliations

Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Naringin in Aged Rats

Xuan Zeng et al. Front Pharmacol. .

Abstract

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.

Keywords: ADME; LC-MS/MS; aged rats; naringenin; naringin.

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Figures

Figure 1
Figure 1
Plasma concentration-time curve of naringin and total naringenin in aged rats after a single oral administration of 42 mg/kg naringin.
Figure 2
Figure 2
Tissue distribution profiles of naringin (A) and total naringenin (B) in aged rat at different time points after a single oral administration of 42 mg/kg naringin.
Figure 3
Figure 3
AUC (female)/AUC (male) (shown in lg) of naringin and total naringenin in tissues collected from aged rats.
Figure 4
Figure 4
Proposed metabolic pathways of flavonoid metabolites in aged rats after a single oral dose of 42 mg/kg naringin. The number of metabolites in the bracket was corresponding to that in Supplementary Table S3.
Figure 5
Figure 5
Proposed pathways for the catabolism of hesperetin by intestinal microbiota and phase II enzymes in aged rats after a single oral dose of 42 mg/kg naringin. Red arrows represent microbiota-mediated steps, while blue arrows indicate rat enzyme-mediated conversions. The number of metabolites in the bracket was corresponding to that in Supplementary Table S4.
Figure 6
Figure 6
Accumulative excretion of naringin (NG) and its main metabolites [naringenin (NE), hesperetin (HE), apigenin (AE), hippuric acid (HA), 4-hydroxybenzonic acid (4HBA), and 3-(4′-hydroxyphenyl)propionic acid (4HPPA)] in urine (A) and feces (B) after a single oral administration of 42 mg/kg naringin to aged rats.
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