Absorption of chlorogenic acid and caffeic acid in rats after oral administration

Absorption of orally administered chlorogenic acid (5-caffeoylquinic acid) and caffeic acid in rats was studied to obtain plasma pharmacokinetic profiles of their metabolites. Rats were administered 700 micromol/kg body weight of chlorogenic or caffeic acid, and blood was collected from the tail for 6 h after administration. Ingested caffeic acid was absorbed from the alimentary tract and was present in the rat blood circulation in the form of various metabolites. On the other hand, only traces of metabolites, supposedly caffeic and ferulic acids conjugates, were detected in rat plasma for 6 h after chlorogenic acid administration. Chlorogenic acid and small amounts of caffeic acid were found in the small intestine for 6 h after chlorogenic acid administration. These results suggest that chlorogenic acid is not well absorbed from the digestive tract, unlike caffeic acid, and subject to almost no structural changes to the easily absorbed forms.     

Enhanced absorption of anthocyanins after oral administration of phytic acid in rats and humans

Many studies on the bioavailability of polyphenols have been reported. However, the relative urinary excretions of AC are also low, ranging from 0.004% to 0.1%. By contrast, other polyphenols show higher urinary excretion levels. Here, we studied the enhancing effects of phytic acid (IP6) on absorption of blackcurrant anthocyanins (BCAs) in rats and humans. In rats after oral administration of BCAs (as 241 mg of AC/kg body weight) in IP6 (0%, 0.25%, 0.5%, 1%, 2.5%) solution, the ACs recovery in urine was increased dependent on IP6 dose. These results suggest that the IP6 enhances gastrointestinal absorption of ACs. At the further analysis of IP6 enhancement effect in rat, whereas BCAs were normally passed through the stomach and duodenum within 2 h, in IP6 group, after 2-6 h post-administration, stomach and jejunum content's weights were specifically heavy, and large amounts of ACs were also detected in stomach, duodenum, and jejunum. These results suggested that the mixture of BCAs and IP6 reduced the gastrointestinal motility. Prolongation of ACs residue in gastrointestinal tract then caused the enhancing effects of IP6 on absorption of AC. In the human study, each subject was orally administrated a BCA beverage containing BCA concentrate (AC 4 mg/kg body weight), 1% of IP6, and 1% of sodium citrate as a pH stabilizer. Both the plasma level and the urinary excretion of AC were increased as compared to BCA administration without IP6. AC intake with IP6 may increase the bioavailability of AC to the comparative level as other polyphenols. Yet, phytic acid, being a strong chelator of important minerals, contributes to mineral deficiencies. An interference with iron uptake has been reported. Safety tests are therefore necessary before high dose IP6 can be used in foods.     

Pharmacokinetics and distribution of [35S]methylsulfonylmethane following oral administration to rats

Methylsulfonylmethane (MSM) is a sulfur-containing compound found in a wide range of human foods including fruits, vegetables, grains, and beverages. More recently, it has been marketed as a dietary supplement worldwide. The objective of this study was to evaluate the pharmacokinetic profile and distribution of radiolabeled MSM in rats. Male Sprague-Dawley rats were administered a single oral dose of [35S]MSM (500 mg/kg), and blood levels of radioactivity were determined at different time points for up to 48 h. Tissue levels of radioactivity at 48 and 120 h and urine and fecal radioactivity levels were measured at different time points for up to 120 h following [35S]MSM administration to rats. Oral [35S]MSM was rapidly and efficiently absorbed with a mean tmax of 2.1 h, Cmax of 622 microg equiv/mL, and AUC0-inf of 15124 h.microg equiv/mL. The t1/2 was 12.2 h. Soft tissue distribution of radioactivity indicated a fairly homogeneous distribution throughout the body with relatively lower concentrations in skin and bone. Approximately 85.8% of the dose was recovered in the urine after 120 h, whereas only 3% was found in the feces. No quantifiable levels of radioactivity were found in any tissues after 120 h, indicating complete elimination of [35S]MSM. The results of this study suggest that [35S]MSM is rapidly absorbed, well distributed, and completely excreted from the body.     

Absorption and bioavailability of artepillin C in rats after oral administration

Artepillin C (AC), an active ingredient of Brazilian propolis, permeates intact across Caco-2 cells by transcellular passive diffusion. The permeation of AC across Caco-2 cells is as efficient as that of phenolic acids and the microbial metabolites of poorly absorbed polyphenols, which are actively absorbed by the monocarboxylic acid transporter (MCT) (Biochim. Biophys. Acta 2005, 1713, 138-144). Here, the absorption of orally administered AC in rats has been studied to evaluate its pharmacokinetics and bioavailability in vivo in comparison with those of p-coumaric acid (CA), a substrate of MCT. Rats were given 100 micromol/kg of body weight of AC or CA, and blood was subsequently collected from the portal vein and abdominal artery. AC, CA, and their metabolites were quantified by coulometric detection using HPLC-ECD. The serum concentration of intact AC and CA in the portal vein peaked at 5-10 min after administration, with a C(max) of 19.7 micromol/L for AC and 74.8 micromol/L for CA. The area under the curve (AUC) for intact AC and CA in the portal vein was calculated from the serum concentration as 182.6 and 3057.3 micromol.min.L(-1), respectively. The absorption efficiency of CA was about 17-fold higher than that of AC. Furthermore, the bioavailability of CA was about 278-fold higher than that of AC, and the ratio of AUC in the abdominal artery to AUC in the portal vein was 0.04 and 0.70, for AC and CA, respectively. Thus, AC is likely to be more susceptible to hepatic elimination than is CA. The bioactive compound of AC in vivo should be investigated further.     

Intestinal absorption of p-coumaric and gallic acids in rats after oral administration

Ferulic acid (FA) and p-coumaric acid (CA) are absorbed by the monocarboxylic acid transporter (MCT) in Caco-2 cells, although gallic acid (GA) is not. Therefore, the MCT is selective for certain phenolic acids. Absorption of orally administered CA and GA in rats was studied to obtain serum pharmacokinetic profiles and to investigate their intestinal absorption characteristics in vivo. Rats were administered 100 micromol/kg body weight of CA and GA, and blood was collected from the portal vein and abdominal artery after administration. CA, GA, and their metabolites were quantified with a highly selective and sensitive coulometric detection method using high-performance liquid chromatography-electrochemical detection. Ingested CA was rapidly absorbed in the gastrointestinal tract in an intact form. The serum concentration of intact CA in the portal vein peaked 10 min after dosing (C(max) was 165.7 micromol/L). In contrast, GA was slowly absorbed, with a t(max) for intact GA of 60 min and a C(max) of 0.71 micromol/L. The area under the curve for intact CA and GA was calculated from the serum concentration profile in the portal vein to be 2991.3 and 42.6 micromol min L(-)(1), respectively. The relative bioavailability of CA against GA was about 70. This is the first demonstration that absorption efficiency of CA is much higher than that of GA in vivo. The absorption characteristics of CA are clearly different from those of GA. These findings are in good agreement with the results obtained in vitro using a Caco-2 cell system.     

Pharmacokinetic study of caffeic and rosmarinic acids in rats after oral administration

p-Coumaric and ferulic acid are actively taken up by monocarboxylic acid transporter (MCT), whereas gallic acid, caffeic acid (CA), and rosmarinic acid (RA) are absorbed by paracellular diffusion in human intestinal Caco-2 cells, although CA has low affinity for MCT. We previously demonstrated that p-coumaric acid has a much higher absorption efficiency than gallic acid in rats, owing to the MCT-mediated absorption of p-coumaric acid in vivo (J. Agric. Food Chem. 2004, 52, 2527-2532). Here, absorption of orally administered CA and RA in rats has been studied to investigate their intestinal absorption characteristics and pharmacokinetics in vivo and to compare the results with those of p-coumaric and gallic acids obtained under identical conditions. Rats were given 100 micromol/kg body weight of CA and RA, and blood was collected from the portal vein and abdominal artery after administration. CA, RA, and their metabolites were quantified by a coulometric detection method using HPLC-ECD. The serum concentration of intact CA and RA in the portal vein peaked at 10 min after administration, with a C(max) of 11.24 micromol/L for CA and 1.36 micromol/L for RA. The area under the curve (AUC) for intact CA and RA in the portal vein was calculated from the serum concentration-time profile to be 585.0 and 60.4 micromol min L-1, respectively. The absorption efficiency of CA was about 9.7-fold higher than that of RA. Overall, the absorption efficiency of these compounds in vivo increases in the order: gallic acid = RA < CA < p-coumaric acid, which is in good agreement with results obtained in Caco-2 cells in vitro.     

Bioaccumulation of melamine in catfish muscle following continuous, low-dose, oral administration

In this study, catfish muscle was analyzed for melamine (MEL) and cyanuric acid (CYA) residues following experimental feeding with low doses of MEL and MEL and CYA (MEL+CYA) and with the insoluble melamine-cyanurate complex (MEL=CYA). Catfish were daily fed 0.1 mg/kg BW of MEL for 15, 28, or 42 days, 0.1 mg/kg BW of MEL+CYA for 28 days, 2.5 mg/kg BW of MEL+CYA for 14 days, or 400 mg/kg BW of MEL=CYA for 3 days. Residues in the tissue were determined by LC-MS/MS. MEL was extracted with acidic acetonitrile, followed by defatting with dichloromethane, and isolated with cation exchange solid phase extraction (SPE). For CYA analysis, fish were extracted with dilute acetic acid, defatted with hexane, and cleaned up with a graphitic carbon SPE. Catfish fed 0.1 mg/kg BW of MEL reached a maximum muscle residue concentration of 0.33 ± 0.04 mg/kg (ppm) after 28 days of continuous feeding. The same concentration was found for MEL+CYA feeding at the 0.1 mg/kg BW level for 28 days. Feeding at 2.5 mg/kg BW of MEL+CYA yielded muscle concentrations above the 2.5 mg/kg level of concern for most of the study fish. Finally, catfish fed high levels of the MEL=CYA complex (400 mg/kg BW) accumulated relatively little MEL in the muscle (0.14 ± 0.07 mg/kg) and, unlike treatment with MEL+CYA, did not form renal melamine-cyanurate crystals. Appreciable concentrations of CYA were not detected in any of the muscles tested. These studies provide data to model the bioaccumulation of triazine residues into edible fish tissue as a result of the continuous consumption of adulterated feed.     

Liquid chromatographic analysis of incurred amoxicillin residues in catfish muscle following oral administration of the drug

Improper application of antibiotic chemicals to livestock and aquaculture species may lead to the occurrence of residues in food supplies. An appropriate depletion period is needed after the administration of drugs to animals for ensuring that residues in edible tissues are below established tolerance levels. This study was conducted to determine incurred amoxicillin residues in catfish muscle following oral administration. Dosed fish were harvested after four depletion periods, and muscle fillets were analyzed for amoxicillin residues using an HPLC method with precolumn derivatization and fluorescence detection. The residue levels in fish after a 6-h depletion ranged from 40 to 64 ng/g with one exception at 297 ng/g. Average residue levels decreased to 5.4 and 2. 8 ng/g after 24- and 48-h depletions, respectively. Residue levels after a 72-h depletion decreased to below the method's limit of quantitation (1.2 ng/g). An LC-MS/MS confirmatory method was developed. Confirmation of the presence of amoxicillin was demonstrated in incurred fish samples containing residues at approximately 50-300 ng/g.     

Toxico-kinetics, recovery, and metabolism of napropamide in goats following a single high-dose oral administration

Toxicokinetic behavior, recovery and metabolism of napropamide (a pre-emergent herbicide) and its effect on Cytochrome P(450) of liver microsomal pellet were studied following a single high-dose oral administration of 2.5 g kg(-1) and continuous (7 days) oral administration of 500 mg kg(-1) in black Bengal goat. Napropamide was detected in blood at 15 min and the maximum quantity was recovered at 3 h after administration. The absorption rate constant (Ka) value was low indicating poor absorption from the gastrointestinal tract. High elimination half-life (t(1/2) beta) and low body clearance (Cl(B)) values coupled with higher transfer of compound from tissue to central compartment (K(21)) suggest that napropamide persisted in the blood for a long time, i.e., after 72 h of oral administration. The recovery percentage of napropamide, including metabolites, from goats varied from 75.94 to 80.08 and excretion of the parent compound through feces varied from 18.86 to 21.59%, indicating that a major portion of the orally administered napropamide was absorbed from the gastrointestinal tract of goat. Napropamide significantly increased the Cytochrome P(450) content of liver microsomal pellet. The recovery of metabolites from feces, urine, and tissues ranged from 4.2--6.2, 40.81--49.42, and 2.7--11.6%, respectively, during a 4--7 day period. The material balance of napropamide (including metabolites) following a single high-dose oral administration at 2.5 g kg(-1) during 4--7 days after dosing was found to be in the range of 75--80%.     

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.     

Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs

The purpose of this study was to determine the absorption, distribution and excretion of (99m)technetium-labeled, high-molecular-weight hyaluronan (((99m)Tc-HA) and (99m)technetium pertechnetate ((99m)Tc-P) after single dose, oral administration to Wistar rats and Beagle dogs. A pilot study utilized (99m)Tc-HA alone, and a second confirmatory study compared uptake of labeled (99m)Tc-HA with (99m)Tc-P. Urinary and fecal excretion after (99m)Tc-HA ingestion by rats showed 86.7-95.6% of radioactivity was recovered, almost all in feces. All tissues examined showed incorporation of radioactivity from (99m)Tc-HA starting at 15 min and persisting for 48 h, in a pattern significantly different from (99m)Tc-P. Whole-body scintigraphs and close-ups of the ventral chest region showed nonalimentary radioactivity from (99m)Tc-HA concentrated in joints, vertebrae and salivary glands four hours after administration. Autoradiography of skin, bone and joint tissue pieces after 24 h showed incorporation of radioactivity from (99m)Tc-HA, but not from (99m)Tc-P. Conversely, absorption, distribution and excretion of (99m)Tc was completely different from (99m)Tc-HA, showing an expected pattern of rapid absorption and excretion in urine, with accumulation in thyroid glands, stomach, kidney and bladder. This report presents the first evidence for uptake and distribution to connective tissues of orally administered, high-molecular-weight HA.     

Metabolism of metamitron in goat following a single oral administration of a nontoxic dose level: a continued study

Disposition kinetic behavior and metabolism studies of metamitron and its metabolite in terms of the parent compound were carried out in black Bengal goats after a single oral administration of a nontoxic oral dose at 30 mg kg(-1) of body weight. Metamitron was detected in the blood sample at 5 min (2.23 +/- 0.04 microg mL(-1)), maximum at 1 h (3.43 +/- 0.02 microg mL(-1)) and minimum at 12 h (0.41 +/- 0.01 microg mL(-1)), after a single oral administration. Metabolite [3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one] in terms of the parent compound was detected in the blood sample at 5 min (0.47 +/- 0.006 microg mL(-1)), maximum at 6 h (5.12 +/- 0.02 microg mL(-1)) and minimum at 96 h (1.06 +/- 0.016 microg mL(-1)), after a single oral administration. The t(1/2 K) and Cl(B) values of metamitron were 3.63 +/- 0.05 h and 1.36 +/- 0.016 L kg(-1) h(-1), respectively, whereas the t(1/2K)(m) and Cl(B)(m) values of the metabolite were 38.15 +/- 0.37 h and 0.091 +/- 0.001 L kg(-1) h(-1), respectively, which suggested long persistence of the metabolite in blood and tissues of goat. Metamitron was excreted through feces and urine for up to 48 and 72 h, whereas the metabolite was excreted for up to 168 and 144 h, respectively. Metabolite alone contributed to 96 and 67% of combined recovery percentage of metamitron and metabolite against the administered dose in feces and urine of goat, respectively. All of the goat tissues except lung, adrenal gland, ovary, testis, and mammary gland retained the metabolite residue for up to 6 days after administration.     

Residue depletion of nitrovin in chicken after oral administration

In this study, the residue depletion of nitrovin in chicken was studied after feeding the birds with dietary feeds containing 10 mg/kg of nitrovin for 7 consecutive days. Tissues (muscle, fat, kidney, and liver) and plasma were collected at different withdrawal periods and determined by a high-performance liquid chromatography-ultraviolet (HPLC-UV) method. The limit of detection for nitrovin in tissue and plasma samples was 0.1 ng/(g or mL), and the inter- and intrarecoveries from the blank fortified samples were in the range of 71.1-85.7%. At the withdrawal period of 0 days, the residue concentration of nitrovin in plasma was the highest (average of 84.98 ng/mL) compared to those in muscle, fat, liver, and kidney (average of 21.04, 61.18, 24.04, and 68.28 ng/g, respectively). At the withdrawal period of 28 days, the residue levels of nitrovin in muscle, fat, liver, and plasma were all higher than 1.0 ng/(g or mL) and the highest concentration was in liver (average of 5.8 ng/g). These data are in support of the ban of nitrovin as a feed additive in food-producing animals.     

Fate of nitrogen in cattle slurry following surface application or injection to grassland

Two field experiments commencing in winter (December) and spring (April) were conducted to determine the fate of nitrogen (N) in cattle slurry following application to grassland. In each experiment three methods of application were used: surface application, and injection ± the nitrification inhibitor, nitrapyrin. Slurry was applied at 80t ha⁻¹, (≡248 kg total N ha⁻¹ in the winter experiment, and 262 kg N ha⁻¹ in the spring experiment). From slurry applied to the surface, total losses of N through NH₃ volatilization, measured using a system of wind tunnels, were 77 and 53 kg N ha⁻¹ respectively for the winter and spring experiments. Injection reduced the total NH₃ volatilization loss to ∼2 kg N ha ⁻¹. Following surface application, loss by denitrification, measured using an adaptation of the acetylene-inhibition technique, was 30 and 5 kg N ha⁻¹ for the two experiments. Larger denitrification losses were observed for the injected treatments; in the winter experiment the loss from the injected slurry without nitrapyrin was 53 kgN ha ⁻¹, and with nitrapyrin 23 kgN ha⁻¹. Total denitrification losses for the corresponding injected treatments in the spring experiment were 18 and 14 kg N ha ⁻¹. Apparent recoveries of N in grass herbage in both experiments broadly reflected the differences between treatments in total gaseous loss.     

Cytoprotective effect of hydroxytyrosyl alkyl ether derivatives after oral administration to rats in a model of glucose-oxygen deprivation in brain slices

This study was designed to determine whether the oral administration of hydroxytyrosol (HT) alkyl ether derivatives has a neuroprotective effect in rats. The animals were treated for 7 days with HT or ethyl, butyl, hexyl, octyl, and dodecyl HT ether. A method of in vitro hypoxia-reoxygenation in brain slices was used. Hexyl, octyl, and dodecyl HT derivatives reduced brain cell death (LDH efflux). Lipid peroxidation and nitrite concentrations were inhibited most by hexyl, octyl, and dodecyl derivatives. Concentrations of 3-nitrotyrosine were reduced by HT butyl, hexyl, octyl, and dodecyl ether derivatives. Interleukin-1β was significantly reduced in brain slices from rats treated with all HT ether derivatives. LDH efflux showed a linear correlation with brain concentrations of lipid peroxides, nitrites plus nitrates, and interleukin 1β. The reduction in oxidative and nitrosative stress and decreased production of pro-inflammatory interleukins may be the basis for the observed neuroprotective effects.     

Avenanthramides are bioavailable and accumulate in hepatic, cardiac, and skeletal muscle tissue following oral gavage in rats

Avenanthramides (AVA), polyphenols found exclusively in oats ( Avena sativa L.), may play a role in the anti-inflammatory and antiatherogenic activity of oats. The bioavailability of AVA has been demonstrated previously, but its distribution at the organ and tissue level and the extent of conjugation following ingestion have been unexplored. Synthetic AVA was administered to 24 rats by oral gavage, whereas 6 control rats received saline. AVA concentrations were measured via HPLC in plasma, liver, heart, and gastrocnemius (GAS) obtained over a 12 h period (0, 2, 4, 12 h; n = 6 at each time point). Samples were extracted with and without glucuronidase-sulfatase to assess the level of conjugation. We conclude that AVA are bioavailable to the blood circulation following oral ingestion in the rat and reach peripheral tissues where they can be taken up by various organs differentially. With AVA remaining in the organs for up to 12 h, it seems possible to maintain an increased level of AVA in the rat via repeated feedings.