Apigenin In Rats Research Articles

Role of Apigenin in Rats with Type 1 Diabetic Complications

Abstract Background and Aim The main factor contributing to diabetes morbidity and mortality is cardiovascular problems. Apigenin, a naturally occurring flavonoid with anti-inflammatory and anti-diabetic characteristics, was investigated for its cardioprotective potential. Methods Type 1 diabetes model was induced using single injection of streptozotocin and diabetic rats were injected with apigenin. ECG recording and measurement of blood pressure were performed. Biochemical analyses of serum glucose, lipid profile, and creatine kinase were done. Histological examination of cardiac tissues was also performed. Results Diabetic rats had higher levels of glucose and creatine kinase, and impaired lipid profile as compared to the control group. Apigenin improved glycemic control, dyslipidemia, and cardiac function markers. Diabetic group had significantly higher blood pressure values as compared to the control group. The mean systolic and diastolic blood pressure levels dropped after apigenin treatment. ECG showed decrease in heart rate and increase in R-voltage after apigenin-injection as compared to diabetic rats. Moreover, apigenin-injection resulted in reduced histological changes of cardiac tissues compared to diabetic rats. Conclusion Apigenin could serve as potential therapeutic agent to reverse effects of hyperglycemia and its cardiovascular complications in diabetes.

Apigenin attenuates high-fat diet-induced nephropathy in rats by hypoglycemic and hypolipidemic effects, and concomitant activation of the Nrf2/antioxidant axis

• The protective potential of apigenin in rats with high-fat diet (HFD)-induced nephropathy by activation of Nrf2. • Apigenin reduced body weight. • Apigenin improved hyperglycemia, hyperinsulinemia, hyperlipidemia and renal tubular damage. • Apigenin increased the mRNA, cytoplasmic, and nuclear levels of Nrf2. • Apigenin reduced levels of GSH, SOD, CAT, MDA, TNF-α, IL-6. This study examined the protective potential of apigenin in rats with high-fat diet (HFD)-induced nephropathy, and tested its involvement in the activation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Control, apigenin, HFD, HFD + apigenin, and HFD + Nrf2 inhibitor (brusatol) groups were formed. Apigenin was administered orally (50 mg/kg), and all treatments were conducted for 12 weeks. Apigenin, administered orally (50 mg/kg), significantly reduced body weight and reversed hyperglycemia, hyperinsulinemia, hyperlipidemia, renal tubular damage, and interstitial collagen deposition induced by HFD-fed rats. Additionally, apigenin significantly increased the mRNA, cytoplasmic, and nuclear levels of Nrf2 and levels of glutathione, superoxide dismutase, and catalase, but significantly reduced the levels of malondialdehyde, tumor necrosis factor-alpha, and interleukin-6, nuclear levels of nuclear factor kappa beta p65, and mRNA levels of transforming growth factor-β1, Bax, and caspase-3. Brusatol co-treatment abolished all the effects of apigenin on these markers, except for body and fat weights, glucose, and insulin. In conclusion, apigenin attenuated HFD-induced nephropathy by activating Nrf2.

LC-MS/MS Determination of Apigenin in Rat Plasma and Application to Pharmacokinetic Study.

Apigenin, a natural plant flavone, has been shown to possess a variety of biological properties. In this report, a highly selective and sensitive LC-MS/MS method was developed and validated for the determination of apigenin in rat plasma. Analysts were separated on the HSS T3 column (1.8 μm 2.1×100 mm) using acetonitrile and 0.1% formic acid in 2mM ammonium acetate buffer at a supply rate of 0.200 mL/min as eluent in gradient model. Plasma samples were treated by protein precipitation using acetonitrile for the recovery ranging from 86.5% to 90.1% for apigenin. The calibration curves followed linearity in the concentration range of 0.50-500ng/mL. The inter-day and intra-day precisions at different QC levels within 13.1% and the accuracies ranged from -10.6% to 8.6%. The assay has been successfully applied to the pharmacokinetic study of apigenin in rats.

Effects of friedelin on the intestinal permeability and bioavailability of apigenin.

Although apigenin possesses diverse pharmacological activities, its utilization as a bioactive substance is limited by poor oral bioavailability. The aim of this study was to improve the bioavailability of apigenin by co-administration of friedelin. To achieve this, the intestinal permeability of apigenin in the absence or presence of friedelin was investigated in both Caco-2 cells and single-pass rat intestinal perfusion models. The apparent permeability coefficients (Papp) of apigenin in the presence of friedelin were substantially increased by 1.63- and 1.60-fold in Caco-2 cells and single-pass rat intestinal perfusion models, respectively. Such increases in the Papp indicated that friedelin could significantly enhance the absorption of apigenin into the body. The increased bioavailability of apigenin in rats following the oral administration of apigenin 50mg/kg body weight with friedelin 50mg/kg body weight was further confirmed by increases in the peak concentration of apigenin (Cmax), elimination half-life (T1/2) and area under the plasma concentration-time curve (AUC). Friedelin suppressed ATPase activity of P-glycoprotein (P-gp) indicated that the improved bioavailability of apigenin may be ascribed to P-gp inhibition by the co-administered friedelin.

Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system

The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus® and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5 nm) and spherical shape at ratio of 4:1 (Soluplus®:Pluronic F127), as well as increasing solubility of to 5.61 mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus® and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract.

Neuroprotective effect of apigenin in rats after contusive spinal cord injury

Apigenin, a common plant flavonoid, has been extensively studied and showed a wide variety of beneficial effects. The aim of this study was to determine the therapeutic efficacy of starting apigenin treatment 3day after spinal cord injury (SCI) in rat and to investigate the underlying mechanism. SCI was induced using the modified weight-drop method in Sprague-Dawley rats. The SCI animals were randomly assigned to five groups: sham control group, SCI model group, the methylprednisolone sodium succinate (MPSS) group, the 10mg/kg apigenin treatment group and the 20mg/kg apigenin treatment group. First, neuronal function after SCI was evaluated with Basso Beattie Bresnahan locomotor rating scale (BBB) and the result showed that injured animals treated with apigenin showed a significant increase in BBB scores. To explore the underlying mechanism, antioxidative effect of apigenin was assessed by measuring malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities after SCI. Apigenin treatment reversed the decrease of SOD and GSH-Px activity, and the increase of MDA level caused by SCI, suggesting its antioxidative role in response to the injury. In addition, apigenin treatment decreased serum interleukin-1β, tumor necrosis factor-α and intercellular adhesion molecule-1 release after SCI, suggesting an anti-inflammatory effect of apigenin. Finally, apigenin treatment affected the expression level of apoptosis-related gene Bax, Bcl-2 and caspase-3, which indicated its antiapoptosis role after SCI. Our data suggest that apigenin significantly promotes the recovery of rat neuronal function after SCI, which is associated with its antioxidative, anti-inflammatory and antiapoptotic properties.

Study on intestinal absorption kinetics of apigenin in rats

To establish an in situ single-way intestinal perfusion model, in order to study the intestinal absorption kinetics of AP. The concentration of AP in the perfusate was determined by HLPC. The results showed different AP concentrations in all intestinal segments, with the fastest absorption rate in duodenum, which was followed by jejunum, ileum and colon. In general, the constant absorption rate (Ka) of AP in duodenum and jejunum first increased and then decreased with the rise in drug concentration (P <0. 05); the absorption mechanism may be related to active transport and facilitated diffusion factors. The constant absorption rate (Ka) of AP in ileum and colon generally kept unchanged with the rise diffusion in drug concentration, the absorption mechanism may be related to passive.

Biopharmaceutics classification and intestinal absorption study of apigenin

The aim of the study was to characterize the biopharmaceutics classification system (BCS) category of apigenin (AP) using intrinsic dissolution rate (IDR) and rat intestinal permeability, and to investigate the intestinal absorption mechanism of AP in rats. In the present investigation, equilibrium solubility and intrinsic dissolution rate (IDR) of AP were estimated in phosphate buffers. Effective intestinal permeability (P(eff)) of AP was determined using single-pass intestinal perfusion (SPIP) technique in four segments (duodenum, jejunum, ileum and colon) of rat intestine at three concentrations (10, 50 and 100 μg/ml). The aqueous solubility of AP in tested phosphate buffers was very poor with maximum solubility of 2.16 μg/ml at pH 7.5. The IDR of AP was very low with a value of 0.006 mg/min/cm(2). The minimum and maximum P(eff)s determined by SPIP were 0.198×10(-4) and 0.713×10(-4) cm/s at jejunum and duodenum site, respectively. In addition, the concentration-dependent permeability behavior was observed in the duodenum and jejunum, which suggested that AP was transported by both passive and active carrier-mediated saturable mechanism in these two intestinal segments. However, the observed concentration-independent permeability behavior in ileum and colon indicated primarily passive transport mechanism of absorption of AP in the last two intestinal segments. AP was classified as class II drug of the BCS due to its low solubility and high intestinal permeability. AP could be well absorbed in the whole intestine with the main absorption site at duodenum. The absorption of AP in four intestinal segments exhibited different transport mechanisms.

The Exposure of Luteolin Is Much Lower than That of Apigenin in Oral Administration of Flos Chrysanthemi Extract to Rats

Luteolin (3',4',5,7-tetrahydroxyflavone) and apigenin (4',5,7-trihydroxyflavone) are two common flavones and major bioactive components in Flos Chrysanthemi extract (FCE). Although FCE contains approximately equal amounts of luteolin (6.5%, w/w) and apigenin (5.4%, w/w), luteolin showed a much lower exposure than apigenin when FCE was orally administered to rats. The aim of the present study is to elucidate the mechanisms that caused the pharmacokinetic difference between luteolin and apigenin in rats. The results of an in situ rat intestinal single-pass perfusion model showed that the permeability of luteolin (k(a), 7.96×10⁻² min⁻¹ and P(eff), 4.87×10⁻³ cm/min) was about 50% that of apigenin (k(a), 18.5×10⁻² min⁻¹ and P(eff), 10.8×10⁻³ cm/min), which agreed with the observation that oral bioavailability of luteolin (30.4%) from FCE was significantly lower than that of apigenin (51.1%). On the other hand, luteolin was much more unstable than apigenin during the incubation with primary rat hepatocytes, and methylated metabolites of luteolin were detected after incubation. In addition, further metabolism of methylated luteolin also contributed to the faster elimination of luteolin. In conclusion, luteolin and apigenin are very similar in structure, however, one-hydroxyl difference gives them different characteristics in absorption and metabolism, which results in much lower exposure of luteolin than apigenin when FCE is orally administered to rats.

Absorption and Excretion of Luteolin and Apigenin in Rats after Oral Administration of Chrysanthemum morifolium Extract

Chrysanthemum morifolium extract (CME) has the protective effect on cardiovascular diseases. Luteolin and apigenin are two major bioactive components in vivo when CME is orally administrated to experimental animal. The present paper shows the study of the absorption and excretion of luteolin and apigenin in rats after a single oral dose of CME (200 mg/kg). The levels of luteolin and apigenin in plasma, urine, feces, and bile were measured by HPLC after deconjugation with hydrochloric acid or beta-glucuronidase/sulfatase. The results showed that the plasma concentrations of luteolin and apigenin reached the highest peak level at 1.1 and 3.9 h after dosing, respectively. The area under the concentration-time curves (AUC) for luteolin and apigenin were 23.03 and 237.6 microg h mL-1, respectively. The total recovery of the dose was 37.9% (6.6% in urine; 31.3% in feces) for luteolin and 45.2% (16.6% in urine; 28.6% in feces) for apigenin. The cumulative luteolin and apigenin excreted in the bile was 2.05% and 6.34% of the dose, respectively. All of the results suggest apigenin may be absorbed more efficiently than luteolin in CME in rats, and both luteolin and apigenin have a slow elimination phase, with a quick absorption, so a possible accumulation of the two flavonoids in the body can be hypothesized.