Pharmacokinetics of Hydroxytyrosol and Its Sulfate and Glucuronide Metabolites after the Oral Administration of Table Olives to Sprague-Dawley Rats.

The pharmacokinetics (PK) of hydroxytyrosol and its metabolites were characterized following oral administration to Sprague-Dawley rats of 3.85 and 7.70 g of destoned Arbequina table olives/kg. Plasma samples were analyzed using a fully validated method consisting of liquid extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis of hydroxytyrosol demonstrated linear PK between doses of 2.95 and 5.85 mg hydroxytyrosol/kg. Half-life was approximately 2.5 h, while mean residence time was around 4 h. Clearance occurred by conversion to two sulfate and two glucuronide conjugates. The area under the plasma concentration-time curve (AUC) ratios of metabolites versus parent hydroxytyrosol was approximately 7-9-fold for the sulfate and below 0.25 for the glucuronide, indicating sulfation as the predominant metabolic pathway. Despite extensive metabolism, hydroxytyrosol remained in plasma for up to 8 h with AUCs of 4293 and 8919 min·nmol/L for the doses of 3.85 and 7.70 g/kg, respectively. Therefore, table olives provide a more sustained plasma profile than other foods containing hydroxytyrosol, which may enhance its health-protecting activities.

Dietary intake of table olives exerts antihypertensive effects in association with changes in gut microbiota in spontaneously hypertensive rats.

Arbequina table olive (AO) consumption lowers blood pressure (BP) in spontaneously hypertensive rats (SHR). This study evaluates whether dietary supplementation with AO induced changes in the gut microbiota that are consistent with the purported antihypertensive effects. Wistar-Kyoto rats (WKY-c) and SHR-c received water, while SHR-o were supplemented by gavage with AO (3.85 g kg-1) for 7 weeks. Faecal microbiota was analysed by 16S rRNA gene sequencing. SHR-c showed increased Firmicutes and decreased Bacteroidetes compared to WKY-c. AO supplementation in SHR-o decreased BP by approximately 19 mmHg, and reduced plasmatic concentrations of malondialdehyde and angiotensin II. Moreover, reshaped faecal microbiota associated with antihypertensive activity by lowering Peptoniphilus and increasing Akkermansia, Sutterella, Allobaculum, Ruminococcus, and Oscillospira. Also promoted the growth of probiotic strains of Lactobacillus and Bifidobacterium and modified the relationship of Lactobacillus with other microorganisms, from competitive to symbiotic. In SHR, AO promotes a microbiota profile compatible with the antihypertensive effects of this food.

Table olive elicits antihypertensive activity in spontaneously hypertensive rats.

BACKGROUND: Table olives are a food with a high content of bioactive compounds with cardioprotective properties, such as oleic acid, polyphenols, and pentacyclic triterpenes. Here, we investigate the effect of the intake of table olives on blood pressure (BP) and body weight in spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar Kyoto (WKY) rats. 'Arbequina' table olives (3.85 g kg-1 ) were administered by gavage to SHR and WKY rats in short-term (1 day) and long-term (7 weeks) experiments. BP was measured by the tail-cuff method, and polyphenols and triterpenes were determined in olives and plasma by liquid chromatography-mass spectrometry. RESULTS: Administration of 'Arbequina' olives to WKY rats did not exert any change in BP in any of the experiments. However, in SHR, the single dose induced a transient reduction in BP of approximately 15 mmHg, from the second to the tenth hour after the administration. In the long-term assay, a similar decrease was established in the second week and was maintained throughout the experiment. Moreover, the daily administration of olives to rats did not affect their body weight when compared with controls in either the WKY rats or SHR. The determination of polyphenols and triterpenes in plasma indicated that, at the end of the experiment, only maslinic acid, oleanolic acid, hydroxytyrosol, and luteolin were found, all of them being compounds with already described capacity to decrease BP. CONCLUSION: The results suggest that the daily intake of table olives could decrease BP in hypertension without affecting body weight, indicating that table olives could contribute to improving cardiovascular health. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Simultaneous Determination of Phenolic Compounds in Plasma by LC-ESI-MS/MS and Their Bioavailability after the Ingestion of Table Olives.

The role attributed to polyphenols on human health needs to be correlated with their plasmatic concentrations after food consumption. Then, a method based on liquid-liquid extraction followed by highly sensitive LC-ESI-MS/MS analysis was developed to determinate 16 phenolic compounds in plasma. Validation gave appropriate recovery, matrix effect (80%-120%), linear correlation (R2 > 0.995), precision (<15%), LOQ (0.04-2.51 nM), and short chromatographic run. The method was verified after the administration of Arbequina table olives to rats. A single dose of destoned olives was given by gavage, and plasmatic concentrations of polyphenols were analyzed at 30 min. Interestingly, the profile found in plasma greatly differed from that of the olives. Plasmatic concentrations, from highest to lowest, were salidroside, p-coumaric acid, hydroxytyrosol, verbascoside, tyrosol, luteolin, and luteolin-7-O-glucoside. In conclusion, a simple and robust method was developed, enabling the identification and quantification of unaltered polyphenols in plasma after olives consumption, thus demonstrating its suitability for pharmacokinetics studies.

Table olive polyphenols: A simultaneous determination by liquid chromatography-mass spectrometry.

Table olives contain a wide range of polyphenols responsible for protective effects on health that have been associated with a lower prevalence of chronic diseases. A new method to identify and quantify these compounds in table olives, by means of methanol:ethanol (1:1; v/v) extraction followed by LC-ESI-MS/MS, has been developed and validated. The chromatographic column Eclipse-XDB-C18, never used before in this kind of application, provided the best results using Milli-Q water with 0.025% acetic acid and acetonitrile with 5% acetone as eluents. This method allows the quantification of 17 polyphenols, namely, hydroxytyrosol, tyrosol, salidroside, hydroxytyrosol acetate, catechol, vanillic acid, caffeic acid, o-coumaric acid, p-coumaric acid, verbascoside; oleuropein; pinoresinol, apigenin, luteolin, luteolin-7-O-glucoside, quercetin and rutin. The new method has been validated and shows linear correlations (R2>0.996), recoveries superior to 95%, high sensitivity, adequate precision and accuracy (RSD < 15%) as well as a short chromatographic analysis of 9 min. Its application to the analysis of Marfil table olives enabled the quantification of 15 polyphenols, among which hydroxytyrosol (384.1 ±â€¯81.2 mg/kg), tyrosol (201.2 ±â€¯3.8 mg/kg), luteolin (88.0 ±â€¯3.8 mg/kg) and salidroside (85.9 ±â€¯3.2 mg/kg) stand out. Furthermore, this method allows to assess whether the intake of a certain number of olives can meet the health claim associated to olive oil polyphenols (Reg. EU n.432/2012). Our results indicate that the daily intake of only 7 olives, which corresponds to 8 g of edible portion, provide an amount of hydroxytyrosol and derivatives (e.g. oleuropein complex and tyrosol) of 5 mg, according to the health claim of the EU. In view of the results, it could be stated that table olives are an excellent source of bioactive compounds, thus emerging as a promising functional food.

Reduction of Preneoplastic Lesions Induced by 1,2-Dimethylhydrazine in Rat Colon by Maslinic Acid, a Pentacyclic Triterpene from Olea europaea L.

Maslinic acid triggers compelling antiproliferative and pro-apoptotic effects in different human cancer cell lines. Hence, the chemopreventive activity was investigated on early stages of carcinogenesis induced by 1,2-dimethylhydrazine (DMH) which is a model that mimics human sporadic colorectal cancer. Male Sprague-Dawley rats were orally administered either maslinic acid at 5, 10 or 25 mg/kg dissolved in (2-hydroxypropyl)-ß-cyclodextrin 20% (w/v) or the solvent for 49 days. After one week of treatment, animals received three weekly intraperitoneal injections of DMH at the dose of 20 mg/kg. Maslinic acid reduced the preneoplastic biomarkers, aberrant crypt foci (ACF) and mucin-depleted foci (MDF), already at 5 mg/kg in a 15% and 27%, respectively. The decline was significant at 25 mg/kg with decreases of 33% and 51%, respectively. Correlation analysis showed a significant association between the concentrations of maslinic acid found in the colon and the reduction of ACF (r = 0.999, P = 0.019) and MDF (r = 0.997, P = 0.049). The present findings demonstrate that maslinic acid induced an inhibition of the initiation stages of carcinogenesis. The assessment of this pentacyclic triterpene at the colon sheds light for designing diets with foods rich in maslinic acid to exert a chemopreventive activity in colorectal cancer.

A sensitive liquid chromatography-mass spectrometry method for the simultaneous determination in plasma of pentacyclic triterpenes of Olea europaea L.

Table olives are especially rich in pentacyclic triterpenic compounds, which exert several biological activities. A crucial step in order to know if these compounds could contribute to the beneficial and healthy properties of this food is their measurement in blood. Therefore, the present study describes a simple and accurate liquid-liquid extraction followed by LC-QqQ-MS analysis for the simultaneous determination of the main pentacyclic triterpenes from Olea europaea L. in rat plasma. The method was validated by the analysis of blank plasma samples spiked with pure compounds, obtaining a linear correlation, adequate sensitivity with a limit of quantification ranging from 1nM for maslinic acid to 10nM for uvaol. Precision and accuracy were lower than 10% in all cases and recoveries were between 95 and 104%. The oral administration of olives to rats and its determination in plasma verified that the established methodology is appropriate for bioavailability studies.

Identification of gut-derived metabolites of maslinic acid, a bioactive compound from Olea europaea L.

SCOPE: Maslinic acid has been described to exert a chemopreventive activity in colon cancer. Hereby, we determined maslinic acid and its metabolites in the rat intestine previous oral administration as a first step in elucidating whether this triterpene might be used as a nutraceutical. METHODS AND RESULTS: Maslinic acid was orally administered at 1, 2, and 5 mg/kg to male Sprague-Dawley for 2 days. At 24 h after the last administration, the content of the duodenum and jejunum, ileum, cecum, and colon was collected and extracted with methanol 80% prior to LC-APCI-MS analysis. The developed method was validated providing suitable sensitivity (LOQ of 5 nM), good recovery (97.8 ± 3.6%), linear correlation, and appropriate precision (< 9%). Maslinic acid was detected in all the segments with higher concentrations in the distal part of the intestine. LC-APCI-LTQ-ORBITRAP-MS allowed the identification of 11 gut-derived metabolites that were formed by mono-, dihydroxylation, and dehydrogenation reactions. CONCLUSION: Maslinic acid undergoes phase I reactions resulting in a majority of monohydroxylated metabolites without the presence of phase II derivatives. The high concentration of maslinic acid achieved in the intestine suggests that it could exert a beneficial effect in the prevention of colon cancer.

Pentacyclic triterpene in Olea europaea L: A simultaneous determination by high-performance liquid chromatography coupled to mass spectrometry.

Pentacyclic triterpenes are gaining interest due to their beneficial health effects, as anti-inflammatory, anti-diabetic and anti-tumoral, among others. In this study, an analytical LC-MS method was developed for the simultaneous determination of maslinic, oleanolic and ursolic acids along with erythrodiol and uvaol, which are the main triterpenic compounds present in the fruits and leaves of Olea europaea L. A Zorbax Eclipse PAH column at 30°C with mobile phase of water (17%) and methanol (83%) at 0.8mL/min conformed the optimal chromatographic conditions that allowed the separation of the compounds of interest, two pairs of which are isomers differing only in the position of one methyl group (oleanolic-ursolic and erythrodiol-uvaol). The ionization was performed in an APCI source at 450°C programmed in negative mode for the triterpenic acids, and in positive for the alcohols. An ion trap (LC-IT-MS) and a triple quadrupole (LC-QqQ-MS) were assessed for maximal sensitivity that was achieved with LC-QqQ-MS. The LODs of triterpenic acids were lower than 1nM, whereas for erythrodiol and uvaol were 4.5 and 7.5nM, respectively. The method was linear for the five analytes in the range of concentrations from 0.005 to 15µM with correlation coefficients exceeding 0.99. The precision and accuracy were ≤9.90% and ≤9.57%, respectively. The applicability of the validated method was assessed in the analysis of the pentacyclic triterpenes in Marfil table olives, after the optimization of the extraction procedure. The developed method constitutes the first step for future studies of triterpenic compounds present in foods that would allow establishing their effects on human health.

Identification in Rat Plasma and Urine by Linear Trap Quadrupole-Orbitrap Mass Spectrometry of the Metabolites of Maslinic Acid, a Triterpene from Olives.

Maslinic acid is a natural pentacyclic triterpenoid widely distributed in edible and medicinal plants with health-promoting activities. The identification and quantification of its metabolites is a requirement for a better understanding of the biological effects of this triterpene. Therefore, maslinic acid was orally administered to Sprague-Dawley rats at a dose of 50 mg/kg of body weight. Blood and urine were withdrawn at 45 min. Samples were extracted with ethyl acetate prior to liquid chromatography-atmospheric pressure chemical ionization-linear trap quadrupole-Orbitrap (LC-APCI-LTQ-Orbitrap) analysis. Screening of plasma yielded four monohydroxylated derivatives (M1-M4), one monohydroxylated and dehydrogenated metabolite (M5), and two dihydroxylated and dehydrogenated compounds (M6 and M7). In urine, M1, M4, M5, and M6 were detected. Quantification by LC-APCI-mass spectrometry (MS) revealed maslinic acid as the prevalent compound in both plasma (81.8%) and urine (73.9%), which indicates that metabolism is low and mainly attributable to phase I reactions.

Maslinic acid, a natural phytoalexin-type triterpene from olives--a promising nutraceutical?

Maslinic acid is a pentacyclic triterpene found in a variety of natural sources, ranging from herbal remedies used in traditional Asian medicine to edible vegetables and fruits present in the Mediterranean diet. In recent years, several studies have proved that maslinic acid exerts a wide range of biological activities, i.e. antitumor, antidiabetic, antioxidant, cardioprotective, neuroprotective, antiparasitic and growth-stimulating. Experimental models used for the assessment of maslinic acid effects include established cell lines, which have been often used to elucidate the underlying mechanisms of action, and also animal models of different disorders, which have confirmed the effects of the triterpene in vivo. Overall, and supported by the lack of adverse effects in mice, the results provide evidence of the potential of maslinic acid as a nutraceutical, not only for health promotion, but also as a therapeutic adjuvant in the treatment of several disorders.

Population pharmacokinetics of maslinic acid, a triterpene from olives, after intravenous and oral administration in rats.

SCOPE: Maslinic acid is a bioactive minor component of Olea europaea L. with health-enhancing activities and no harmful effects. A pharmacokinetic (PK) study was conducted to determine its bioavailability for future studies of maslinic acid in humans. METHODS AND RESULTS: Intravenous (1 mg/kg) and oral (50 mg/kg) administrations to Sprague-Dawley rats were performed. Blood was obtained several times over 24 h and PKs were analyzed with NONMEM 7.2, applying a population approach. Body weight was included a priori in the model with fixed allometric exponents, based on allometric principles. Plasma concentrations versus time were best characterized by a two-open compartment model with first-order absorption and linear elimination. Maslinic acid had a relative rapid oral absorption with a peak concentration after administration at 0.51 h and a bioavailability of 5.13%. Once in bloodstream, it distributed extensively into tissues, since the central and peripheral distribution volumes were 8.41 L/70 kg and 63.6 L/70 kg, respectively. The clearance (8 L/h/70 kg) was related to unaltered renal excretion. The prediction-corrected visual predictive check confirmed its stability and predictive ability. CONCLUSION: An allometric population PK model was performed for maslinic acid, which adequately described and predicted plasma concentrations.

Liquid chromatography-mass spectrometry determination in plasma of maslinic acid, a bioactive compound from Olea europaea L.

Maslinic acid, a pentacyclic triterpene from Olea europaea L., exerts hypoglycemic, antioxidant, cardioprotective and antitumoral activities. Here, an LC-APCI-MS method to determine this compound in plasma is presented as a first step in pharmacokinetic studies. Maslinic acid was extracted from plasma with ethyl acetate and separated on a C18 column using a gradient elution of water and acetonitrile. The target ions were m/z 471.3 for maslinic acid and m/z 455.3 for I.S. The method was validated by the analysis of spiked plasma samples obtaining a linear correlation, a recovery of 99.0±0.9% and a quantification limit of 5 nM. The precision and accuracy were ≤8.38% and ≤4.82%, respectively. Finally, the method was verified by measuring the rat plasmatic concentrations 24h after the single oral administration of 10, 25 and 50 mg/kg of maslinic acid, thereby ensuring that the procedure is appropriate for its use in bioavailability studies.

Assessment of the safety of maslinic acid, a bioactive compound from Olea europaea L.

SCOPE: Maslinic acid, the main pentacyclic triterpene of the cuticle of Olea europaea L. fruit, has multiple beneficial effects on health, most notably antitumor and hypoglycemic properties. Notwithstanding the biological activities, there is a lack of knowledge about its safety. Therefore, the purpose of this study was to evaluate whether high doses of maslinic acid have harmful effects on Swiss CD-1 male mice. METHODS AND RESULTS: The single oral administration of the pentacyclic triterpene at 1000 mg/kg to mice did not produce any signs of morbidity or mortality. The repeated daily oral administration of 50 mg/kg of maslinic acid for 28 days did not induce any sign of toxicity during the experimental period. Body weight did not differ between mice that received the triterpene and the control group. Similarly, hematological and biochemical variables were not affected by the treatment. Histopathologic examination of the organs revealed that there were no differences between the control and the treated mice. CONCLUSION: Taken together the results obtained from the acute and the repeated intake of maslinic acid indicate that the compound does not exert any adverse effects on the variables tested in mice, thus suggesting a sufficient margin of safety for its putative use as a nutraceutical.

Determination of maslinic acid, a pentacyclic triterpene from olives, in rat plasma by high-performance liquid chromatography.

Maslinic acid, a pentacyclic triterpene from olives, has been reported to exert beneficial effects on health, including anticarcinogenic activity. Despite its importance, little is known about its bioavailability in both humans and animals. A fundamental step for this evaluation consisted of measuring this compound in blood. Therefore, a simple high-performance liquid chromatography (HPLC) method with diode array detection has been developed. Maslinic acid contained in plasma was extracted twice using ethyl acetate. After centrifugation, the organic fraction was evaporated to dryness and the residue was reconstituted with methanol/water (75:25, v/v) and analyzed by HPLC. The method was validated by obtaining a linear correlation (r(2) = 0.999) and an average recovery of 99%. Precision expressed as the coefficient of variation ranged from 1.23 to 9.06%. The oral administration of maslinic acid (50 mg/kg) to rats and its subsequent detection in plasma showed that the method is suitable for absorption, distribution, and metabolism studies.

The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters.

The ABC proteins are a family of membrane transporters that mediates the extrusion from cells of a wide variety of structurally unrelated substrates. The current review focuses on the role of these efflux pumps located in the intestine on the low oral bioavailability of trans-resveratrol. The enterocytes hold in the apical membrane three transporters, namely, P-glycoprotein (P-gp), multidrug resistance associated protein 2 (MRP2) and breast cancer resistance protein (BCRP), whereas the basolateral membrane contains multidrug resistance associated protein 3 (MRP3). The use of different specific inhibitors of these transporters as well as knockout mice enabled us to conclude that MRP2 and BCRP are involved in the extrusion of trans-resveratrol glucuronide and sulfate to the intestinal lumen without the participation of P-gp. The role of these transporters as a bottleneck in the absorption of trans-resveratrol cannot be undervalued affecting not only the bioavailability of its glucuronide and sulfate but also their distribution in the different organs.

Colorectal cancer chemoprevention by trans-resveratrol.

trans-Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural phytoalexin present in grapes, red wine, berries and peanuts with health protecting properties. The low oral bioavailability indicated for this polyphenol, with the intestine as a bottleneck to its absorption, has promoted the large intestine as a potential target site for its chemopreventive activity. This review recapitulates the current evidence of the effects of trans-resveratrol on colon cancer. First, we describe the studies conducted in vitro which show that the protective activity takes place by inhibition of proliferation and induction of apoptosis. Secondly, the chemopreventive activity in animal models of colon carcinogenesis is revised. trans-Resveratrol not only reduces the number of preneoplastic lesions but also the incidence and multiplicity of tumors. Lastly, the article also reviews the available data on clinical trials. Altogether, the present findings support the hypothesis that the oral administration of trans-resveratrol might contribute to the prevention of colon carcinogenesis.

D-Fagomine lowers postprandial blood glucose and modulates bacterial adhesion.

D-Fagomine is an iminosugar originally isolated from seeds of buckwheat (Fagopyrum sculentum Moench), present in the human diet and now available as a pure crystalline product. We tested D-fagomine for activities connected to a reduction in the risk of developing insulin resistance, becoming overweight and suffering from an excess of potentially pathogenic bacteria. The activities were: intestinal sucrase inhibition in vitro (rat mucosa and everted intestine sleeves), modulation of postprandial blood glucose in rats, bacterial agglutination and bacterial adhesion to pig intestinal mucosa. When ingested together with sucrose or starch, D-fagomine lowered blood glucose in a dose-dependent manner without stimulating insulin secretion. D-Fagomine reduced the area under the curve (0-120 min) by 20 % (P < 0·01) and shifted the time to maximum blood glucose concentration (Tmax) by 15 min at doses of 1-2 mg/kg body weight when administered together with 1 g sucrose/kg body weight. Moreover, D-fagomine (0·14 mm) agglutinated 60 % of Enterobacteriaceae (Escherichia coli, Salmonella enterica serovar Typhimurium) populations (P < 0·01), while it did not show this effect on Bifidobacterium spp. or Lactobacillus spp. At the same concentration, d-fagomine significantly (P < 0·001) inhibited the adhesion of Enterobacteriaceae (95-99 % cells in the supernatant) and promoted the adhesion of Lactobacillus acidophilus (56 % cells in the supernatant) to intestinal mucosa. D-Fagomine did not show any effect on bacterial cell viability. Based on all this evidence, D-fagomine may be used as a dietary ingredient or functional food component to reduce the health risks associated with an excessive intake of fast-digestible carbohydrates, or an excess of potentially pathogenic bacteria.

Retinol-binding protein 4 and peroxisome proliferator-activated receptor-γ in steatotic liver transplantation.

Numerous steatotic livers are discarded for transplantation because of their poor tolerance of ischemia-reperfusion (I/R). The injurious effects of retinol-binding protein 4 (RBP4) in various pathologies are well documented. RBP4 levels are reduced by peroxisome proliferator-activated receptor-γ (PPARγ) agonists. Strategies aimed at increasing PPARγ protect steatotic livers under warm ischemia. Ischemic preconditioning (PC) based on brief periods of I/R protects steatotic liver grafts against I/R injury, but the responsible mechanism is poorly understood. We examined the roles of RBP4 and PPARγ in I/R injury associated with steatotic liver transplantation and the benefits of PC in such situations. We report that RBP4 and PPARγ expression levels in nonsteatotic livers were similar to those found in the sham group. However, reduced RBP4 and increased PPARγ levels were observed in steatotic livers. Treatment with either RBP4 or a PPARγ antagonist was effective only in steatotic livers. PC, which increased RBP4 levels, and RBP4 treatment both reduced PPARγ levels and hepatic injury in steatotic livers. When PPARγ was activated, neither RBP4 treatment nor PC (despite RBP4 induction) protected steatotic livers. In conclusion, steatotic liver grafts are more predisposed to down-regulate RBP4 and overexpress PPARγ. RBP4 treatment and PC, through RBP4 induction, reduced PPARγ levels in steatotic liver grafts, thus protecting them from the PPARγ detrimental effects.

Population pharmacokinetic modeling of trans-resveratrol and its glucuronide and sulfate conjugates after oral and intravenous administration in rats.

PURPOSE: To develop a population pharmacokinetic (PK) model which allowed the simultaneous modeling of trans-resveratrol and its glucuronide and sulfate conjugates. METHODS: Male Sprague-Dawley rats were administered i.v. and p.o. with 2, 10 and 20 mg·kg(-1) of trans-resveratrol. Blood was collected at different times during 24 h. An integrated PK model was developed using a sequential analysis, with non-linear mixed effect modeling (NONMEM). A prediction-corrected visual predictive check (pcVPC) was used to assess model performance. The model predictive capability was also evaluated with simulations after the i.v. administration of 15 mg·kg(-1) that were compared with an external data set. RESULTS: Disposition PK of trans-resveratrol and its metabolites was best described by a three-linked two-compartment model. Clearance of trans-resveratrol by conversion to its conjugates occurred by a first-order process, whereas both metabolites were eliminated by parallel first-order and Michaelis-Menten kinetics. The pcVPC confirmed the model stability and precision. The final model was successfully applied to the external data set showing its robustness. CONCLUSIONS: A robust population PK model has been built for trans-resveratrol and its glucuronide and sulfate conjugates that adequately predict plasmatic concentrations.