Geniposide In Rats Research Articles

Oral chronic toxicity study of geniposide in rats

Ethnopharmacological relevanceGeniposide, the major active constituent of Fructus Gardeniae (FG), has been widely used to treat various diseases in China. Aim of the studyThis chronic toxicity study was conducted to investigate the safety of geniposide. Materials and methodsGeniposide was administered to Sprague-Dawley (SD) rats of both sexes by oral gavage at dosages of 25, 50, or 100mg/kg in a volume of 10mL/kg once daily for 26 weeks. Endpoints included clinical observations, food consumption, body weights, blood biochemistry, haematology, and histomorphological observations. ResultsThe administration of geniposide did not influence animal mortality, the general conditions of the animals, body weights or food consumption. After 4 weeks of administration, significant toxicity was not observed. However, in the 13th week of the toxicity study, a few haematological parameters and some relative organ weights of male rats in the 50 and 100mg/kg geniposide groups were significantly increased. The percentage of reticulocytes (Retic %) was significantly increased in male and female rats administered 100mg/kg geniposide. In addition, two female rats in the 100mg/kg geniposide group showed slight pathological changes in hepatic and renal tissues. Furthermore, in a chronic (26 weeks) toxicity study, differences were detected in alanine aminotransferase (ALT), aspartate aminotransferase (AST), sodium (Na+), potassium (K+), white blood cell (WBC), red blood cell (RBC), and haemoglobin (HGB) levels and the relative weights of the liver and spleen in male rats administered 100mg/kg geniposide. In addition, differences were detected in Retic % and the relative weights of the liver, thymus, and kidneys in female rats administered 100mg/kg geniposide. Urinalysis results from male and female rats in the 100mg/kg geniposide group revealed noticeable changes. The histopathological structures of hepatic and renal tissues in the high-dose geniposide group exhibited serious abnormalities and pigment deposition. ConclusionGeniposide affected serum biochemistry, urinalysis, and haematological parameters as well as relative organ weights. The treatment also caused noticeable pathological abnormalities in liver and kidney tissues. Therefore, administration of a high dose of geniposide (100mg/kg) for 26 weeks could induced obvious liver and kidney damage.

Metabolite profile analysis and pharmacokinetic study of emodin, baicalin and geniposide in rats

1. Emodin, baicalin and geniposide are the major bioactive components in Da-Huang, Huang-Qin and Zhi-Zi which are herbal medicines widely used in Asian nations.2. The metabolism of the three compounds was found to undergo hydroxylation, decarboxylation, dehydration, methylation, hydrolysis, hydrogenation, dihydrogenation, sulfation, glucosidation and/or glucuronidation. A total of 63 metabolites were detected in urine, plasma and bile of rats given a mixture of the three compounds.3. Pharmacokinetic properties of the three compounds were determined in rats given the extracts of Da-Huang, Huang-Qin and Zhi-Zi. The pharmacokinetic parameters for emodin, baicalin and geniposide were found to be 0.13 ± 0.11, 0.25 ± 0.12 and 0.40 ± 0.09 h (Tmax); 21 ± 9, 1515 ± 254 and 482 ± 50 ng/mL (Cmax); 8.6 ± 5.5, 18.3 ± 2.8 and 22.1 ± 17.2 h (t1/2); 29 ± 20, 16886 ± 3734 and 2936 ± 551 ng/mLċh (AUC(0–t)); and 37 ± 20, 22624 ± 6295 and 3582 ± 820 ng/mLċh (AUC(0–∞)).4. The metabolism and pharmacokinetic studies facilitate appropriate employment of Da-Huang, Huang-Qin and Zhi-Zi in clinic.

Comprehensive characterization of the in vitro and in vivo metabolites of geniposide in rats using ultra-high-performance liquid chromatography coupled with linear ion trap–Orbitrap mass spectrometer

1. Geniposide (genipin 1-O-glucose), one of the major bioactive constituents isolated from Fructus Gardeniae, possesses many biological activities. In this study, an efficient strategy was developed using ultra-high-performance liquid chromatography coupled with linear ion trap–Orbitrap mass spectrometer (UPLC–LTQ–Orbitrap) to profile the in vitro and in vivo metabolic patterns of geniposide in rat liver microsomes (RLMs), plasma, urine, and various tissues. And post-acquisition data-mining methods including extracted ion chromatogram (EIC), multiple mass defect filters (MMDF), fragment ion searching (FISh), and isotope pattern filtering (IPF) were adopted to characterize the known and unknown metabolites.2. A total of 33 metabolites were detected and interpreted according to accurate mass measurement, diagnostic fragment ions, relevant drug biotransformation knowledge, and bibliography data. Among them, 17 metabolites were detected in the plasma, 31 metabolites were identified in the urine, six metabolites could be found in rat heart, 12 in liver, three in spleen, six in lung, 12 in kidney, six in brain, and four in RLMs.3. A series of corresponding reactions such as hydrolysis, hydroxylation, taurine conjugation, hydrogenation, decarboxylation, demethylation, sulfate conjugation, cysteine S-conjugation, glucosylation, and their composite reactions were all discovered.4. The results could provide comprehensive insights and guidance for elucidation of side effect mechanism and safety monitoring as well as for rational formulation design in drug delivery system. The newly discovered geniposide metabolites could be targets for future metabolism studies on the important chemical constituents from herbal medicines.

Identification and distribution of four metabolites of geniposide in rats with adjuvant arthritis

Geniposide (GE), also called Jasminoidin, is the major active ingredient of Gardenia jasminoides Ellis (GJ) fruit, which has long been used in traditional Chinese medicine (TCM). Growing evidences suggested that GE has a great potentiality for treating rheumatoid arthritis (RA). However, GE is rapidly metabolized, and we know little about its availability or metabolites in tissues. To elucidate the distribution of GE and its metabolites in tissues, three groups of adjuvant arthritis (AA) rats were given GE (33, 66 and 120mg/kg) from days 18 to 24, and the biotransformation of GE in plasma, liver, spleen, synovium, urine and mesenteric lymph node (MLN) of rats was investigated by a novel approach named Information-Dependent Acquisition (IDA)-Mediated LC–MS/MS method. As a result, GE and its four major metabolites were detected as follows: GE, G1, G2 in plasma; GE, G2 in MLNs; only GE in liver and synovium; GE, G2, G3 and G4 in spleen; and GE, G1, G2 and G4 in urine. In total four metabolites (G1–G4) involved in the in vivo metabolism processes were identified. The results of this work have demonstrated the IDA-Mediated LC–MS/MS could screen rapidly and reliably the characterization of metabolites from iridoid compounds.

Pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats

In order to characterize the pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats, a reliable gradient HPLC-based method has been developed and validated. After p.o. administration of geniposide, the peak concentration of geniposide in plasma occurred at 1 h and plasma geniposide was eliminated nearly completely within 12 h. The AUC(0→∞) values of geniposide were 6.99 ± 1.27 h · µg/ml and 6.76 ± 1.23 h · µg/ml after i.v. administration of 10 mg/kg and p.o. administration of 100 mg/kg of geniposide, respectively. The absolute oral bioavailability (%F) of geniposide was calculated as 9.67%. After p.o. administration of geniposide, the AUC(0→4h) values in tissues were in the order of kidney > spleen > liver > heart > lung > brain. This study improved the understanding of the pharmacokinetics, bioavailability and tissue distribution of geniposide in rats and may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines.

Exploratory Pharmacokinetics of Geniposide in Rat Model of Cerebral Ischemia Orally Administered with or without Baicalin and/or Berberine

Huang-Lian-Jie-Du-Tang (HLJDT), a classical Chinese prescription, has been clinically employed to treat cerebral ischemia for thousands of years. Geniposide is the major active ingredient in HLJDT. The aim is to investigate the comparative evaluations on pharmacokinetics of geniposide in MCAO rats in pure geniposide, geniposide : berberine, and geniposide : berberine : baicalin. Obviously, the proportions of geniposide : berberine, geniposide : baicalin, and geniposide : berberine : baicalin were determined according to HLJDT. In our study, the cerebral ischemia model was reproduced by suture method in rats. The MCAO rats were randomly assigned to four therapy groups and orally administered with different prescription proportions of pure geniposide, geniposide : berberine, geniposide : baicalin, and geniposide : berberine : baicalin, respectively. The concentrations of geniposide in rat serum were determined using HPLC, and main pharmacokinetic parameters were investigated. The results indicated that the pharmacokinetics of geniposide in rat serum was nonlinear and there were significant differences between different groups. Berberine might hardly affect the absorption of geniposide, and baicalin could increase the absorption ability of geniposide. Meanwhile, berberine could decrease the absorption increase of baicalin on geniposide.

Pharmacokinetics of Geniposide in Zhi‐Zi‐Hou‐Pu Decoction and in Different Combinations of its Constituent Herbs

Zhi-Zi-Hou-Pu decoction (ZZHPD), a classic antidepressant formula, is composed of Gardenia jasminoides Ellis (ZZ), Fructus aurantii immaturus (ZS) and Cortex magnoliae officinalis (HP). ZZHPD has attracted a great deal of attention for its antidepressant effects. The aim of this study was to compare the pharmacokinetics of geniposide (one of the predominant active ingredients) after oral administration of different combinations of ZZHPD and to explore the influence of herb-herb interaction on the pharmacokinetics of geniposide. Twenty four rats were divided randomly into four groups and were administered one of the four extracts: ZZ, ZZ-HP, ZZ-ZS and ZZHPD (ZZ-HP-ZS) via intragastric gavage with approximately the same dose of 40.65 mg/kg geniposide (an effective human daily dose of ZZHPD). Plasma concentrations of geniposide were determined using an HPLC method. Pharmacokinetic parameters were calculated from the plasma concentration-time data. Compared with ZZ alone, the ZZ-ZS combination delayed T(max) and ZZ-HP, ZZ-ZS, ZZHPD remarkably shortened the T(1/2) of geniposide. In addition, ZZ-HP, ZZ-ZS, ZZHPD obviously increased the AUC of geniposide. The result illustrated that the oral bioavailability of geniposide was dramatically enhanced when ZZ was combined with HP or/and ZS. It can be deduced that herb-herb interaction may increase the absorption, and significantly improve the oral bioavailability of geniposide in rats.

The in situ and in vivo study on enhancing effect of borneol in nasal absorption of Geniposide in rats

The objective of this research was to study the in situ and in vivo nasal absorption of Geniposide (Ge) co-administered with borneol. A rat in situ nasal perfusion technique with a novel volumeadjusted calculation was used to examine the absorption rate and extent of Ge. The influence of different experimental conditions such as purity of extract, drug concentration, co-administration with synthetic borneol or natural borneol were also investigated. Results indicated nasal absorption of Ge was primarily by passive diffusion that resembled first order kinetics. Following co-administration with borenol, the drug absorption was increased by 1.4 and 1.7 folds for natural borneol and synthetic borneol, respectively. However, the effect of other factors on drug absorption was not significant. In addition, it was also observed that there is a positive correlation between the absorption of water and Ge by the nasal route. In vivo studies carried out in rats where Ge was co-administered with NB and the pharmacokinetic profile obtained following intranasal administration were compared with those after intravenous administration. The bioavailability of Ge by intranasal was 101.5% and T(max) was 2.04 +/- 0.64 min. MRT was 218.7 +/- 74.1 min and 44.4 +/- 8.9 min for intranasal and intravenous, respectively. Combined with the borneol, Ge can be promptly and thoroughly absorbed intranasally in rats.

Metabolism and pharmacokinetics of genipin and geniposide in rats

Geniposide, an iridoid glucoside, is a major constituent in the fruits of Gardenia jasminoides (Gardenia fruits), a popular Chinese herb. Genipin, the aglycone of geniposide, is used to prepare blue colorants in food industry and also a crosslinking reagent for biological tissue fixation. In this study, we investigated the metabolism and pharmacokinetics of genipin and geniposide in rats. Blood samples were withdrawn via cardiopuncture and the plasma samples were assayed by HPLC method before and after hydrolysis with sulfatase and β-glucuronidase. The results indicated that after oral administration of genipin or Gardenia fruit decoction, genipin sulfate was a major metabolite in the bloodstream, whereas the parent forms of genipin and geniposide were not detected. Importantly, oral administration of 200 mg/kg of genipin resulted in a mortality of 78% (7/9) in rats.

A 13-week oral dose subchronic toxicity study of gardenia yellow containing geniposide in rats

Gardenia yellow powders A, B and C, containing geniposide at 0.284%, 0.938% and 2.783%, respectively, were administered orally to male and female SD rats as 3% feed admixtures for 13-weeks to evaluate any potential toxicity. Mean geniposide intake values were 5.72, 18.9 and 56.3 mg/kg/day in groups receiving these feed admixtures, respectively. All animals survived the duration of the study. The following findings were evident in the gardenia yellow C group: chromatouria, slightly increased plasma total bilirubin, blackish brown discoloration of the kidneys and liver, brown pigments in the proximal tubular epithelium of the kidneys. Slightly increased plasma total bilirubin was considered to be due to interference of metabolite of geniposide with the system of measurement and not to be a toxic effect since there were no related changes in histopathology of the liver or in any blood chemistry parameters. Other findings were limited to pigmentations or discolorations attributable to metabolites of geniposide. No treatment-related effects were evident on body weight, food consumption, ophthalmology, hematology or organ weights in any group. Therefore, it was concluded that 3-month ingestion of the gardenia yellow powder containing geniposide at 2.783% (approximately 60 mg/kg/day as geniposide intake) does not cause any severe toxic effects.