Abstract: The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.

Abstract: Laura Ehlers and Richard Luthy recently published an important A-page feature in ES&T in which they persuasively make the case that improving risk assessment and remediation rests on better understanding of bioavailability (1). Their article provided a concise summary of a major U.S. National Research Council (NRC) report called Bioavailability of Contaminants in Soils and Sediments: Processes, Tools and Applications (2). Despite consensus by scientists that bioavailability is indeed critical to the risk assessment process, Ehlers and Luthy note that the NRC report contains no explicit definition of bioavailability. Rather, the report defines bioavailability processes as the individual physical, chemical, and biological interactions that determine the exposure of organisms to chemicals associated with soils and sediments.

Abstract: Hypertension or high blood pressure is a significant health problem worldwide. Bioactive peptides that inhibit angiotensin I converting enzyme (ACE) in the cardiovascular system can contribute to the prevention and treatment of hypertension. These ACE inhibitory peptides are derived from many food proteins, especially milk proteins. An ACE inhibitory activity in vitro does not always imply an antihypertensive effect in vivo. Even if it does, it is very difficult to establish a direct relationship between in vitro and in vivo activity. This is mainly due to the bioavailability of the ACE inhibitory peptides after oral administration and the fact that peptides may influence blood pressure by mechanisms other than ACE inhibition. To exert an antihypertensive effect after oral ingestion, ACE inhibitory peptides have to reach the cardiovascular system in an active form. Therefore, they need to remain active during digestion by human proteases and be transported through the intestinal wall into the blood. The bioavailability of some ACE inhibitory peptides has been studied. It is also known that (hydroxy)proline-containing peptides are generally resistant to degradation by digestive enzymes. Peptides can be absorbed intact through the intestine by paracellular and transcellular routes, but the potency of the bioactivity after absorption is inversely correlated to chain length. In addition, some strategies are proposed to increase the bioavailability of ACE inhibitory peptides. Further research into the bioavailability of ACE inhibitory peptides will lead to the development of more effective ACE inhibitory peptides and foods.

Abstract: In mammals, the carnitine pool consists of nonesterified L-carnitine and many acylcarnitine esters. Of these esters, acetyl-L-carnitine is quantitatively and functionally the most significant. Carnitine homeostasis is maintained by absorption from diet, a modest rate of synthesis, and efficient renal reabsorption. Dietary L-carnitine is absorbed by active and passive transfer across enterocyte membranes. Bioavailability of dietary L-carnitine is 54-87% and is dependent on the amount of L-carnitine in the meal. Absorption of L-carnitine dietary supplements (0.5-6 g) is primarily passive; bioavailability is 14-18% of dose. Unabsorbed L-carnitine is mostly degraded by microorganisms in the large intestine. Circulating L-carnitine is distributed to two kinetically defined compartments: one large and slow-turnover (presumably muscle), and another relatively small and rapid-turnover (presumably liver, kidney, and other tissues). At normal dietary L-carnitine intake, whole-body turnover time in humans is 38-119 h. In vitro experiments suggest that acetyl-L-carnitine is partially hydrolyzed in enterocytes during absorption. In vivo, circulating acetyl-L-carnitine concentration was increased 43% after oral acetyl-L-carnitine supplements of 2 g/day, indicating that acetyl-L-carnitine is absorbed at least partially without hydrolysis. After single-dose intravenous administration (0.5 g), acetyl-L-carnitine is rapidly, but not completely hydrolyzed, and acetyl-L-carnitine and L-carnitine concentrations return to baseline within 12 h. At normal circulating l-carnitine concentrations, renal l-carnitine reabsorption is highly efficient (90-99% of filtered load; clearance, 1-3 mL/min), but displays saturation kinetics. Thus, as circulating L-carnitine concentration increases (as after high-dose intravenous or oral administration of L-carnitine), efficiency of reabsorption decreases and clearance increases, resulting in rapid decline of circulating L-carnitine concentration to baseline. Elimination kinetics for acetyl-L-carnitine are similar to those for L-carnitine. There is evidence for renal tubular secretion of both L-carnitine and acetyl-L-carnitine. Future research should address the correlation of supplement dosage, changes and maintenance of tissue L-carnitine and acetyl-L-carnitine concentrations, and metabolic and functional changes and outcomes.

Abstract: Bioavailability is a key pharmacokinetic parameter which expresses the proportion of a drug administered by any nonvascular route that gains access to the systemic circulation. Presented in this review are the different approaches to measurement of bioavailability (absolute and relative), including the case in which intravenous administration is impossible. The rate of drug absorption is also discussed with special emphasis on the possible difficulties encountered using C(max) and T(max) or curve fitting to evaluate the rate of drug absorption.

Abstract: OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic analysis was performed in each patient after oral and subcutaneous administration of the same dose of MTX. MTX serum concentrations were measured by a fluorescence polarization immunoassay. Pharmacokinetic analysis was performed with an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. RESULTS: The median MTX dose was 30 mg weekly (range 25-40 mg). A 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after oral MTX was 0.64 (range 0.21-0.96) compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 administration regimens. CONCLUSION: Bioavailability of a higher oral dose of MTX in adult patients with RA is highly variable, and on average two-thirds that of the subcutaneous administration. To improve efficacy of MTX at dosages of 25 mg weekly or more, a change to parenteral administration should be considered.

Abstract: pdf prediction of the human oral bioavailability by prediction of the human oral bioavailability by using in vitro and in silico drug related parameters in a physiologically based absorption model, drug permeability profiling using cell free permeation cell free permeation systems are gaining interest in drug discovery and development as tools to obtain a reliable prediction of passive intestinal absorption without the disadvantages associated with cell or tissue based permeability profiling, solid dispersions a review on drug delivery system and abstract solid dispersions defined as the dispersion of one or more active pharmaceutical ingredient in a carrier at solid state and an efficient technique to improve dissolution of poorly water soluble drugs to enhance their bioavailability poor water solubility is one of the major problems for the various types of drugs and various approaches have been introduced for the enhancement of, biorelevant media for transport experiments in the caco 2 biorelevant media for transport experiments in the caco 2 model to evaluate drug absorption in the fasted and the fed state and their usefulness, solid dispersions as strategy to improve oral solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs, development characterization and evaluation of the introduction sulfasalazine ssz is widely used to treat ulcerative colitis and crohn s disease ulcerative colitis is caused by inflammation of the large intestine colon and or rectum while crohn s disease causes chronic inflammation mainly in the lower part of the small intestine, erlotinib c22h23n3o4 pubchem erlotinib is a kinase inhibitor the mechanism of action of erlotinib is as a protein kinase inhibitor, directory of in silico drug design tools directory of computer aided drug design tools click2drug contains a comprehensive list of computer aided drug design cadd software databases and web services, fexofenadine c32h39no4 pubchem clinical data from over 2000 patients indicate that fexofenadine hydrochloride lacks the cardiotoxic potential of its parent drug terfenadine in 714 patients with seasonal allergic rhinitis fexofenadine hydrochloride dosages of 60 240 mg twice daily were not associated with statistically significant mean increases in the qt interval corrected for rate qtc in controlled clinical studies, works 1 of sakuma lab setsunan ac jp foreword drug delivery system 31 3 2016 183 258, free access to scientific journals open access journals open access journals are the major source of knowledge for young and aspiring generations who are keen in pursuing a career in sciences this system provides easy access to networks of scientific journals authors that contribute their scholarly works to open access journals gain remarkable reputation as the research scholarly explore these works extensively

Abstract: The environmental risk from soil lead (Pb) is related to its bioavailability. Soil Pb bioavailability depends on the solubility of Pb solid phases and other site-specific soil chemistry, suggesting that in situ stabilization of soil Pb can be accomplished by changing soil Pb chemistry. This paper presents a review of soil Pb bioavailability and an evaluation of in situ stabilization methods that can be used to reduce Pb bioavailability. A promising in situ approach involves the amendment of Pb-contaminated soil with phosphorus (P) in various forms or P with other amendments. Two general categories of P are insoluble forms, such as phosphate rock or synthetic apatites, and soluble forms typically present in commercially available fertilizer products or phosphoric acid. Numerous indirect assessment techniques show marked reductions in soil Pb biovailability upon addition of P and other amendments to Pb-contaminated soils. The techniques include physiologically based extraction tests, plant uptake of Pb, and other soil Pb extraction methods. More directly, animal feeding studies also show reductions in soil Pb biovailability. In situ stabilization of soil Pb using P and other soil amendments is an emerging technology integrating soil chemistry, agricultural practices, and engineering that is gaining public and regulatory acceptance. © 2004 American Institute of Chemical Engineers Environ Prog, 23: 78–93, 2004

Abstract: Ferulic acid (FA) is reported as a good antioxidant absorbed by human or rat but only few data deal with the influence of the food matrix on its bioavailability and with its potential protection against cardiovascular diseases and cancer. Wheat bran is used as a source of ferulic acid, the compound being mainly bound to arabinoxylans of the plant cell walls. Pharmacokinetic profiles of FA and its metabolites are established in rats. Free and conjugated FA quickly appear in plasma, reach a plateau 1 h after intake and remain approximately constant at 1 microM up to 24 h. 2.3% of FA are eliminated in urine. Compared with results obtained after intake of free FA, the presence of FA-arabinoxylans bonds in the food matrix increases the occurrence time of FA in the organism and decreases the level of urinary excretion in 24 h. Nevertheless, sulfated FA is still the main plasmatic form. The antioxidant activity of plasmas of rats fed with a standard diet (containing no FA), pure ferulic acid (5.15 mg FA/kg bw) or bran (4.04 mg FA/kg bw) are measured in an ex vivo test using AAPH as free radical inducer. Plasmas of rats fed with bran show a better antioxidant activity than the control group and the pure FA supplemented group, increasing the resistance of erythrocytes to hemolysis by factors of 2 and 1.5, respectively. These results show the good bioavailability of FA from bran and its potential efficiency to protect organism against pathology involving radical steps of development.

Abstract: The purpose of this study was to investigate the absolute bioavailability of a single oral dose of imatinib (Glivec), 400 mg (capsules vs. oral solution), compared with imatinib, 100 mg (intravenous [i.v.] infusion), in healthy subjects. Twelve subjects received a single treatment in each treatment period: a 400-mg oral dose of imatinib in capsule form or as a solution or a 100-mg i.v. infusion of imatinib. Plasma imatinib concentrations were measured following each treatment; pharmacokinetic parameters and absolute bioavailability were determined. Absolute bioavailability values (compared with i.v. infusion) for the imatinib capsule and oral solution were 98.3% and 97.2%, respectively. Both the rate and extent of imatinib absorption, as measured by C(max), partial AUC, and total AUC, were similar for the oral solution and the imatinib capsule intended for the market. The 400-mg oral dose of imatinib, as a capsule or a solution, was completely absorbed and was almost completely bioavailable (> 97%).

Abstract: Comments and suggestions regarding this draft document should be submitted within 30 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

Abstract: Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

Abstract: We developed a rapid in vitro digestion/Caco-2 cell culture model for assessing relative bioavailabilities of iron in foods and meals. The objective of the present study was to determine how closely our Caco-2 model reflects the human response. Meals described in published reports of studies on effects of varying levels of ascorbic acid (AA) and tannic acid (TA) on iron absorption by human subjects were carefully replicated. Iron absorption ratios (iron absorption from meals containing AA or TA divided by iron absorption from identical meals without these enhancers or inhibitors) were determined using the Caco-2 model. Ferritin formation by the Caco-2 cells was used as an indicator of iron absorption. Response patterns of effects of AA and TA on absorption ratios (AR) calculated from Caco-2 and human data were very similar: AA increased ARs in a dose-response manner and TAs decreased AR. The natural logs of the ARs determined in Caco-2 and human studies were correlated: R = 0.935 (P = 0.012) and 0.927 (P = 0.007) for AA and TA, respectively. When results from meals with AA and TA were pooled, a linear relation between the natural logs of ARs from Caco-2 and human studies was observed (R = 0.968, P < 0.001). We conclude that our Caco-2 model accurately predicts the human response to AA and TA in the meals we tested. If future work reproduces the precision and accuracy shown in this paper for predicting iron bioavailability to humans, then the implications for saving time and resources in iron bioavailability measurements are considerable.

Abstract: The risk posed by soil contaminants strongly depends on their bioavailability. In this study, a partition-based sampling method was applied as a tool to estimate bioavailability in soil. The accumulation of organic micropollutants was measured in two earthworm species (Eisenia andrei and Aporrectodea caliginosa) and in 30-μm poly(dimethylsiloxane) (PDMS)-coated solid-phase micro extraction (SPME) fibers after exposure to two field-contaminated soils. Within 10 days, steady state in earthworms was reached, and within 20 days in the SPME fibers. Steady-state concentrations in both earthworm species were linearly related to concentrations in fibers over a 10 000-fold range of concentrations. Measured concentrations in earthworms were compared to levels calculated via equilibrium partitioning theory and total concentrations of contaminants in soil. In addition, freely dissolved con- centrations of contaminants in pore water, derived from SPME measurements, were used to calculate concentrations in earthworms. ...

Abstract: The absorption of gabapentin (Neurontin) is dose-dependent and variable between patients. Rapid clearance of the drug necessitates dosing three or more times per day to maintain therapeutic levels. These deficiencies appear to result from the low capacity, limited intestinal distribution, and variable expression of the solute transporter responsible for gabapentin absorption. Saturation of this transporter at doses used clinically leads to unpredictable drug exposure and potentially ineffective therapy in some patients. XP13512 [(±)-1-([(α-isobutanoyloxyethoxy)carbonyl]aminomethyl)-1-cyclohexane acetic acid] is a novel prodrug of gabapentin designed to be absorbed by high-capacity nutrient transporters located throughout the intestine. XP13512 was efficiently absorbed and rapidly converted to gabapentin after oral dosing in rats and monkeys. Exposure to gabapentin was proportional to prodrug dose, whereas exposure to intact XP13512 was low. In rats, >95% of an oral dose of 14C-XP13512 was excreted in urine in 24 h as gabapentin. In monkeys, oral bioavailability of gabapentin from XP13512 capsules was 84.2% compared with 25.4% after a similar oral Neurontin dose. Compared with intracolonic gabapentin, intracolonic XP13512 gave a 17-fold higher gabapentin exposure in rats and 34-fold higher in monkeys. XP13512 may therefore be incorporated into a sustained release formulation to provide extended gabapentin exposure. XP13512 demonstrated improved gabapentin bioavailability, increased dose proportionality, and enhanced colonic absorption. In clinical use, XP13512 may improve the treatment of neuropathic pain, epilepsy, and numerous other conditions by increasing efficacy, reducing interpatient variability, and decreasing frequency of dosing.

Abstract: Epidemiological data showed that tomato and tomato product (sauce, paste) consumption is associated with a protective effect against the development of some chronic-degenerative diseases. Tomato antioxidant bioactive molecules such as carotenoids and polyphenols could be responsible, at least in part, for the healthy effect observed. The bioavailability of these compounds is an essential requirement to sustain their in vivo role. While it is well known that many factors can influence the bioaccessibility of carotenoids from the food matrix, there is little information about the factors affecting phenolic compounds’ bioaccessibility. This investigation was carried out to evaluate the effect of domestic cooking on the bioavailability in humans of antioxidant molecules after the administration of a test meal containing cherry tomatoes. A cross-over design was conducted. Subjects (3 females and 2 males) consumed experimental meals containing fresh and cooked cherry tomatoes. Blood collection was performed at different time intervals (0, 2, 4, 6, 8 and 24 h). Carotenoid and phenol plasma concentrations were measured. Plasma levels of lycopene and β-carotene were not significantly different with respect to the baseline after ingestion of both the test meals, while plasma concentrations of naringenin and chlorogenic acid increased significantly with respect to the baseline (P<0.05) after administration of cooked cherry tomatoes, but not after administration of fresh cherry tomatoes. The present study indicated that domestically cooked tomatoes significantly increase naringenin and chlorogenic acid plasma levels. Considering that both naringenin and chlorogenic acid are widely studied for their potential healthy properties, evidence of their bioavailability and of the factors influencing their bioaccessibility is an important tool to sustain the possibility that these polyphenols play a biological role in human physiology.