Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women

ObjectiveTo investigate the pharmacokinetics of 17β-estradiol (E2) administered orally versus those of 17β-E2 administered sublingually in transgender women.MethodsSingle doses of 17β-E2 were administered orally (1 mg) to 10 transgender women and then sublingually (1 mg) after a 1-week washout period. Blood samples were collected at baseline (0 hour) and at 1, 2, 3, 4, 6, and 8 hours after dosing. The samples were frozen and analyzed using liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay.ResultsThe results demonstrated that sublingual E2 had a significantly higher peak serum E2 concentration of 144 pg/mL, measured using LC-MS/MS, compared with an oral E2 concentration of 35 pg/mL, measured using LC-MS/MS (P = .003). Sublingual E2 peaked at 1 hour and oral E2 peaked at 8 hours, as measured using LC-MS/MS. The area under the curve (AUC) (0-8 hours) for sublingual E2, measured using LC-MS/MS, was 1.8-fold higher than the AUC (0-8 hours) for oral E2, measured using LC-MS/MS. Additionally, sublingual E2 was found to have an increased E2-to-estrone ratio at all time points (1.1 ± 1.0 vs 0.7 ± 0.4, P ≤ .0001), the clinical significance of which is unclear.ConclusionOral E2 administered sublingually has a different pharmacokinetic profile, with higher serum E2 levels and AUC (0-8 hours) than traditionally administered oral E2. Multidaily dosing may be necessary to suppress testosterone levels with sublingual E2. The appropriate dosing, efficacy, and safety of sublingual E2, compared with those of other E2 preparations, are unknown.     

Determination of naringin and naringenin in human urine by high-performance liquid chromatography utilizing solid-phase extraction

An HPLC method for determining a flavonoid naringin and its metabolite, naringenin, in human urine is presented for application to the pharmacokinetic study of naringin. Isocratic reversed-phase HPLC was employed for the quantitative analysis by using hesperidin for naringin or hesperetin for naringenin as internal standard and solid-phase extraction using a strong anion exchanger, Sep-Pak Accell QMA cartridge. The HPLC assay was carried out using an Inertsil ODS-2 column (250×4.6 mm I.D., 5 μm particle size). The mobile phases were acetonitrile–0.1 M ammonium acetate–acetic acid (18:81:1, v/v; pH 4.7) for naringin and acetonitrile–0.1 M ammonium acetate–triethylamine (25:75:0.05; v/v; pH 8.0) for naringenin. The flow-rate was 1.0 ml min⁻¹. The analyses were performed by monitoring the wavelength of maximum UV absorbance at 282 nm for naringin and at 324 nm for naringenin. The lower limits of quantification were ca. 25 ng/ml for naringin and naringenin with R.S.D. less than 10%. The lower limits of detection (defined as a signal-to-noise ratio of about 3) were approximately 5 ng for naringin and 1 ng for naringenin. A preliminary experiment to investigate the urinary excretion of naringin, naringenin and naringenin glucuronides after oral administration of 500 mg of naringin to a healthy volunteer demonstrated that the present method was suitable for determining naringin and naringenin in human urine.     

Some new aspects of 17alpha-estradiol metabolism in man

17Alpha-estradiol (1,3,5(10)-estratriene-3,17alpha-diol) together with a tracer dose of the tritium-labeled compound was administered orally and sublingually to male volunteers. The serum concentrations of 17alpha-estradiol (free and liberated by enzymatic hydrolysis) were quantified by GC/MS, and the serum total radioactivity and urinary radioactivity excretion were determined. After oral administration, 17alpha-estradiol was rapidly and intensively conjugated; only tiny quantities of the free steroid (<1% of total) appeared in serum. Sublingual administration resulted in temporary (up to 3 h p.a.) higher serum levels of the free compound. The metabolite patterns obtained by TLC of extracts from serum and urine demonstrated that 17alpha-estradiol is the subject of a poor phase I metabolism in man. A great discrepancy was found in the serum concentrations of 17alpha-estradiol (free + conjugated) determined by GC/MS and the serum radioactivity expressed in 17alpha-estradiol equivalents. By TLC analysis of the steroid conjugates extracted from serum, various 17alpha-estradiol conjugate peaks were found. By enzymatic hydrolysis with beta-glucuronidase/aryl sulfatase from Helix pomatia they were only partially cleaved. Thus, the difference between the serum radioactivity and the 17alpha-estradiol levels determined by GC/MS had to be attributed to an incomplete conjugate hydrolysis. It has been shown with the synthesized 17alpha-estradiol sulfate conjugates that only the 3-sulfate is cleaved by enzymatic hydrolysis, whereas the 17-sulfate group resists enzymatic hydrolysis. The methanolysis procedure (acetyl chloride in MeOH) has proved to be an efficient method for cleaving both the 3-sulfate group and the 17-sulfate group. In contrast to the 17alpha-estradiol conjugates in serum, the urinary conjugates were intensively split by the enzyme preparation. From this, it has to be concluded that the serum conjugates were deconjugated and newly reconjugated before urinary excretion.     

Enhanced Solubility and Bioavailability of Naringenin via Liposomal Nanoformulation: Preparation and <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluations

This study was aimed at preparing orally administered naringenin-loaded liposome for pharmacokinetic and tissue distribution studies in animal models. The liposomal system, consisting of phospholipid, cholesterol, sodium cholate, and isopropyl myristate, was prepared using the thin-film hydration method. Physicochemical characterization of naringenin-loaded liposome such as particle size, zeta potential, and encapsulation efficiency produced 70.53?±?1.71 nm, ?37.4?±?7.3 mV, and 72.2?±?0.8%, respectively. The in vitro release profile of naringenin from the formulation in three different media (HCl solution, pH 1.2; acetate buffer solution, pH 4.5; phosphate buffer solution, pH 6.8) was significantly higher than the free drug. The in vivo studies also revealed an increase in AUC of the naringenin-loaded liposome from 16648.48 to 223754.0 ng·mL^?1 h as compared with the free naringenin. Thus, approximately 13.44-fold increase in relative bioavailability was observed in mice after oral administration. The tissue distribution further showed that the formulation was very predominant in the liver. These findings therefore indicated that the liposomal formulation significantly improved the solubility and oral bioavailability of naringenin, thus leading to wider clinical applications.     

Comparative study on toxicokinetics of bisphenol A in F344 rats, monkeys (Macaca fascicularis), and chimpanzees (Pan troglodytes).

We compared the toxicokinetics of bisphenol A (BPA) among three animal species: rats, cynomolgus monkeys and chimpanzees. Rats and monkeys were administered BPA orally or subcutaneously at 10 or 100 mg/kg body weight, while chimpanzees were administered only 10 mg/kg of BPA. BPA in serum was measured by ELISA. In oral administration of BPA at 10 mg/kg, both C(max) and AUC were rats < chimpanzee < monkeys. In oral administration of BPA at 100 mg/kg, both C(max) and AUC were rats < monkeys. Subcutaneous BPA administrations also revealed similar results, although the values of toxicokinetic parameters in subcutaneous administration were higher than those in oral administration. These results suggest that orally or subcutaneously administered BPA in primates is more easily absorbed than that in rats. We conclude that there are considerable differences in distribution, metabolism, and excretion of BPA between rodents and primates.     

The pharmacokinetics of H2 receptor blocking agents in compensated liver cirrhosis

The bioavailability of oral and intravenous cimetidine and ranitidine was studied in patients with compensated liver cirrhosis. Single doses of 200 and 400 mg cimetidine were used for both administration routes, while ranitidine was administered in doses of 150 mg orally or 50 mg i.v. Plasma concentrations and urinary recovery were determined by the HPLC method. The pharmacokinetics of both of these drugs in the cirrhotic patients did not differ from those found in normal subjects. The two doses of cimetidine given i.v. gave rise to the same plasma concentrations, while after oral administration, 400 mg produced higher plasma concentrations than 200 mg. As to the pharmacokinetic parameters, neither cimetidine nor ranitidine administered i.v. offered any further advantages compared to the oral route. The urinary recovery of both cimetidine and ranitidine was higher after intravenous than after oral administration. It is concluded therefore that the pharmacokinetics of cimetidine and ranitidine is not altered in compensated liver cirrhosis.     

Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma

Curcuminoids, curcumin and its structurally related compounds, constitute the phenolic yellowish pigment of turmeric. We investigated the absorption and metabolism of orally administered curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) in rats. HPLC and LC-MS analyses after enzymatic hydrolyses showed that the predominant metabolites in plasma following administration were glucuronides and glucuronide/sulfates (conjugates with both glucuronide and sulfate) of curcuminoids. The plasma concentrations of conjugated curcuminoids reached a maximum one hour after administration. The conjugative enzyme activities for glucuronidation and sulfation of curcumin were found in liver, kidney and intestinal mucosa. These results indicate that orally administered curcuminoids are absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide and glucuronide/sulfate conjugates.     

Naringinase-catalyzed hydrolysis of naringin adsorbed on macroporous resin

Naringenin, a natural plant flavonoid found in citrus fruits, has been reported to exhibit a wide range of pharmacological functions, including anticancer, antioxidant, antiatherogenic, antithrombotic, and vasodilator activities. Naringenin can be produced from the naringinase (NGase)-catalyzed enzymatic hydrolysis of naringin. However, the poor solubility of naringin in aqueous systems considerably limits the efficiency of naringenin biocatalysis. In this work, a novel substrate adsorption system was proposed for naringin adsorption to increase the efficiency of naringin hydrolysis and naringenin production. Three Amberlite macroporous resins, namely, XAD-4, XAD-7HP and XAD-16, were investigated for their naringin adsorption capacities and effects on NGase hydrolysis. Results indicated that the physical properties of the resins played a critical role in naringin adsorption and naringenin enzymatic synthesis. Naringin hydrolysis was carried out using free and adsorbed substrates. The substrate adsorption strategy could increase the catalytic efficiency at a high naringin concentration. In addition, the reaction conditions for enzymatic naringenin synthesis were optimized, and naringenin was prepared at a liter scale with a high substrate concentration. These results suggested that substrate adsorption is a promising strategy to increase the enzymatic hydrolysis efficiency of naringenin in aqueous systems.     

Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone.

The pharmacokinetics of total and free prednisolone (PSL) in six healthy men, with or without pretreatment with oral glycyrrhizin (GL), was investigated to confirm whether oral administration of GL influences the metabolism of PSL in man. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS) with or without pretreatment with 50 mg of oral GL four times. Blood samples were taken from a peripheral vein at 5, 10, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after the start of PSL-HS infusion. The concentrations of total PSL in plasma were analyzed by high-performance liquid chromatography, and the free PSL was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of PSL were determined by non-compartment analysis. Oral administration of GL was found to significantly increase the concentrations of total PSL at 6, 8 h, and of free PSL at 4, 6 and 8 h after PSL-HS infusion. Moreover, oral administration of GL was also found to modify the pharmacokinetics of both total and free PSL. After oral administration of GL, the area under the curve (AUC) was significantly increased, the total plasma clearance (CL) was significantly decreased, and the mean residence time (MRT) was significantly prolonged. However, the volume of distribution (Vdss) showed no evident change. This suggests that oral administration of GL increases the plasma PSL concentrations and influences its pharmacokinetics by inhibiting its metabolism, but not by affecting its distribution.     

Pharmacokinetics of the beta-carboline norharman in man.

In healthy subjects, pharmacokinetics were characterised using single oral and sublingual administrations of the beta-carboline norharman. For this purpose, norharman levels in blood plasma were measured up to 90-105 min after both routes of administration. Dose proportionality of three different single oral doses of norharman (7, 65 and 110 microg/kg) administered as 0.52 and 5 mg capsules was evaluated at 8 time points. Peak levels were attained at 30 min after the oral load of norharman. Mean relative availabilities determined by the area under the curve (AUC) procedure were 14.3 and 98.0 nmol.min/l after oral dosing of 7 and 65 microg/kg, respectively. AUC values in women were 3-4 times higher than in men. Sublingual dosing of 6.5 and 13 microg/kg norharman encapsulated in 5 mg of cyclodextrins resulted in a much higher mean AUC and a more rapid absorption. Mean AUC after sublingual administration of 6.5 microg/kg was 929.8 nmol.min/kg and plasma levels were maximal 10-15 min after norharman was given. Moreover, apparently no sex difference was found using this way of application. Norharman disappeared from the plasma with half-lifes of 25-35 min, irrespective of the route of administration. Even at the highest measured norharman levels of 53 nmol/l plasma, no behavioral effects were observed. In addition, the subjects did neither report any effects nor any side-effects during the experiment. This is the first study in which the kinetics of ingested norharman have been measured in humans.     

Bioavailability and pharmacokinetics of a praziquantel bolus in kingfish Seriola lalandi

Oral praziquantel (PZQ) preparations have recently been investigated for the treatment of monogeneans that infect the skin and gills of kingfish Seriola lalandi cultured in sea-cages. To evaluate an oral PZQ dosing strategy, the pharmacokinetics of a dissolved and in feed oral PZQ preparation (40 mg kg(-1) body weight) were compared with an intravenous bolus in kingfish plasma and skin using HPLC. Compared with intravenous administration, PZQ bioavailability (area under curve, AUC0-24h) was slightly improved when the drug was administered with food in both kingfish plasma (56.8% in feed vs. 50.8% in solution) and skin (55.5% in feed vs. 50.3% in solution). After oral dosing, maximum drug concentrations in skin were approximately one-third of those achieved in plasma and higher when the drug was administered in solution (5.26 microg ml(-1)) than in feed (3.96 microg ml(-1)); additionally, the time to achieve maximum PZQ concentration was similar in plasma and skin, although markedly reduced when the drug was administered in solution (1 h) than in feed (6 h). However, clearance of the drug was delayed in skin; administered as an oral formulation, PZQ concentrations in the systemic circulation fell below the limit of quantification after 24 h, but remained quantifiable (0.3 microg g(-1)) in skin at this time. These initial studies indicate that a daily treatment interval will lead to the exposure of parasites to highly variable anthelmintic concentrations, which may be sub-optimal for the treatment of monogeneans in this finfish species.     

Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits

The anti-atherogenic effects of the citrus flavonoids, naringin and naringenin, were evaluated in high cholesterol-fed rabbits. At 3 months of age, 30 male New Zealand White (NZW) rabbits were divided into three groups (n = 10 per group). The rabbits were fed a 1% cholesterol diet alone (control group) or a diet supplemented with either 0.1% naringin or 0.05% naringenin for 8 weeks. The plasma lipoprotein levels, total cholesterol, triglyceride, and high-density lipoprotein showed no significant differences in the control and experimental groups. Hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity was slightly low in naringin (5.0%)- and naringenin (15.0%)-fed rabbits, compared to control group. The aortic fatty streak areas were significantly lower in both the naringin (19.2 +/- 5.6%)- and naringenin (18.1 +/- 6.5%)-supplemented groups than in the control group (60.4 +/- 14.0%). The expression levels of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1), by semiquantitative RT-PCR analysis of the thoracic aorta, were significantly lower in the flavonoids supplemented groups than in the control group. These results suggest that the anti-atherogenic effect of the citrus flavonoids, naringin and naringenin, is involved with a decreased hepatic ACAT activity and with the downregulation of VCAM-1 and MCP-1 gene expression.     

Naringenin reduces lung metastasis in a breast cancer resection model

Metastasis is the main cause of death in cancer patients. To improve the outcomes of patients undergoing a surgery, new adjuvant therapies that can effectively inhibit metastases have to be developed. Studies have shown that flavonoid naringenin, a natural product that is mainly present in grapes and citrus, may contribute to cancer prevention. It has many advantages compared to traditional chemotherapeutic drugs, such as low toxicity. To determine whether naringenin can also inhibit metastases, a breast cancer resection model that mimics clinical situations was established. We found that orally administered naringenin significantly decreased the number of metastatic tumor cells in the lung and extended the life span of tumor resected mice. Flow cytometry analysis revealed that T cells displayed enhanced antitumor activity in naringenin treated mice, with an increased proportion of IFN-γ and IL-2 expressing T cells. In vitro studies further demonstrated that relief of immunosuppression caused by regulatory T cells might be the fundamental mechanism of metastasis inhibition by naringenin. These results indicate that orally administered naringenin can inhibit the outgrowth of metastases after surgery via regulating host immunity. Thus, naringenin can be an ideal surgical adjuvant therapy for breast cancer patients.     

Stereoselective pharmacokinetics of indobufen from tablets and intramuscular injections in man

The influence of administration route (oral or intramuscular (i.m.)) on the pharmacokinetics of total indobufen (INDB) enantiomers was studied in healthy volunteers after a 200 mg dose as a single oral tablet or i.m. injection. Enantiospecific reversed phase (RP) HPLC with UV detection was used for the determination of INDB enantiomers in serum. INDB enantiomers were isolated from serum by solid phase extraction (SPE) procedure using C(18) columns. INDB enantiomers were converted to their L-leucinamide diastereoisomers and separated on a C(18) HPLC column. INDB from i.m. injections is absorbed faster (t(max) = 0.6-0.9 h) than from tablets (t(max) = 1.3-1.8 h). The area under curve (AUC) after administration of the tablet was slightly higher than after i.m. injection. The pharmacokinetic behaviour of (+)-S- and (-)-R-INDB after administration of the tablet was different from i.m. injection of racemic INDB. The (+)-S-enantiomer is more rapidly eliminated than its (-)-R-antipode. Statistically significant differences also occurred between enantiomers in AUC, first order elimination rate constant (k), clearance (Cl). The ratio AUC(R):AUC(S) was similar for the tablet (1.57-1.62) and i.m. injection (1.59-1.62). It was concluded that the formulation and extent of ionisation of rac-INDB (acid or sodium salt of INDB) do not significantly influence its stereoselective pharmacokinetics.     

Microbial Transformation of Flavonoids

The ability of a number of fungal spores, and in particular of resting vegetative mycelia, to transform naringin and naringenin was studied. In general, only hydrolytic cleavage of the sugar moieties of naringin to produce prunin and naringenin was observed. Two cultures, Penicillium charlesii and Helminthosporium sativum, also produced two unidentified flavonoid compounds but in very low yields. No transformation of aglycone was detected, although the compound was metabolized by some cultures when supplied as the glycoside prunin. A fluorodensitometric method was developed for the quantitative analysis of flavonoid compounds.     

Influence of the route of administration on the pharmacokinetics of pirprofen enantiomers in the rat

The pharmacokinetics of the enantiomers of the non-steroidal anti-inflammatory drug pirprofen were studied in male Sprague-Dawley rats after oral and intravenous (iv) doses of the racemate. No significant differences were detected between the enantiomers after oral or iv dosing in t_½, Vd, or ∑Xu. However, the R:S area under the plasma concentration (AUC) ratio after oral doses (0.92 ± 0.13) was slightly but significantly lower than after matching iv doses (1.05 ± 0.036). The absolute bioavailability of the active S-enantiomer (78.5%) after oral doses was higher than the inactive R-enantiomer (69.3%). The plasma protein binding of both enantiomers was saturable over a fivefold range of plasma concentrations. At higher plasma concentrations, the S-enantiomer was less bound than the R-enantiomer. In an in vitro experiment using everted rat jejunum, no chiral inversion was discernible. The dependency of the AUC ratio of the enantiomers on the route of administration may be due to stereoselective first-pass metabolism. © 1993 Wiley-Liss, Inc.     

Stereospecific pharmacokinetics and toxicodynamics of ketorolac after oral administration of the racemate and optically pure enantiomers to the rat

To determine the stereospecific pharmacokinetics and gastrointestinal permeability (GI) changes (surrogate measures of toxicity) in the rat following oral administration of S, R, and racemic ketorolac (KT), optically pure enantiomers (S and R 2.5 mg/kg), and racemic KT (5 mg/kg) were administered orally to male Sprague-Dawley rats and plasma samples were collected for 6 h post-dose for pharmacokinetic assessments. KT-induced changes in GI permeability were assessed using sucrose and 51Cr-EDTA as markers of gastroduodenal and distal intestinal permeability, respectively. After the racemate, R-KT was predominant in plasma (AUC S/R, 0.45). No significant differences in pharmacokinetic indices were evident following administration of the racemate as compared with individual enantiomers. In plasma, there was only negligible S-KT after administration of R-KT. After S-KT, on the other hand, AUC of R-KT was found to be 6.7% of that of S-KT. Both permeability markers showed considerable interanimal variability. Gastroduodenal permeability was significantly increased from baseline by the racemate but not by either of the two enantiomers administered alone. Permeability to 51Cr-EDTA was not significantly increased above baseline for any of the treatments. The plasma concentration of R-KT found after administration of S-KT may be from the < 2% chiral impurity which appears magnified due to its slower clearance as compared with its antipode. There is no evidence of a pharmacokinetic interaction between the enantiomers. Since 2.5 mg/kg S-KT is somewhat less toxic on the gastroduodenum than 5 mg/kg racemate, it may be a safer alternative to the latter, at least in the rat model.     

Differential stereoselective pharmacokinetics of pantoprazole,a proton pump inhibitor in extensive and poor metabolizers of pantoprazole—a preliminary study

Pantoprazole (PAN) is a proton pump inhibitor that is administered as a racemic mixture. The pharmacokinetics of PAN enantiomers were investigated in extensive metabolizers (EMs) and apparent poor metabolizers (PMs) of PAN who received a single 40, 60, or 80 mg oral dose of racemic PAN as enteric-coated formulation. In the EMs, the serum concentrations of (−)-PAN were slightly higher than those of (+)-PAN at each dose level. The (+)/(−) ratios for the area under the concentration-time curve (AUC) and the half-life were 0.58–0.89 and 0.62–0.88, respectively. In the PMs, the serum concentrations of both enantiomers were much higher than those in the EMs at each dose level and significant differences in pharmacokinetics of (+)- and (−)-PAN were observed. The half-lives for (+)-PAN were 2.67–3.77 times longer than those for (−)-PAN. The AUCs for (+)-PAN were 2.65–3.45 times greater than those for (−)-PAN. Therefore, the metabolism of (+)-PAN is impaired to a greater extent than (−)-PAN in the PMs, which resulted in the stereoselective disposition of PAN in the PMs. It has been suggested that the EMs and the PMs of PAN could be differentiated by determining the (+)/(−) enantiomer ratio in serum at one time point, possibly 2–6 h after oral dosing, because the (+)/(−) enantiomer ratios in the PMs were opposite those in the EM subjects. Chirality 9:17–21, 1997 © 1997 Wiley-Liss, Inc.     

Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin

The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-β-cyclodextrin (HPβCD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HPβCD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and C(max) increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42% and increased the rate of glucose clearance by 64% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1α in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HPβCD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection.