Abstract: As they persist, or age, in soil, organic compounds become progressively less available for uptake by organisms, for exerting toxic effects, and for biodegradation and bioremediation by microorganisms. This declining bioavailability is not reflected by currently used methods for the chemical analysis of soils for determining concentrations of organic pollutants. As a result, such methods overestimate exposure, and thus risk, from toxic chemicals in contaminated sites.

Abstract: Carotenoids are thought to contribute to the beneficial effects of increased vegetable consumption. Various dietary factors have an effect on the bioavailability of carotenoids. The type of food matrix in which carotenoids are located is a major factor. The bioavailability of beta-carotene from vegetables in particular has been shown to be low (14% from mixed vegetables) compared with that of purified beta-carotene added to a simple matrix (e.g., salad dressing), whereas for lutein, the difference is much smaller (relative bioavailability of 67% from mixed vegetables). Processing, such as mechanical homogenization or heat treatment, has the potential to enhance the bioavailability of carotenoids from vegetables (from 18% to a sixfold increase). The amount of dietary fat required to ensure carotenoid absorption seems low (approximately 3-5 g per meal), although it depends on the physicochemical characteristics of the carotenoids ingested. Unabsorbable, fat-soluble compounds reduce carotenoid absorption, and interaction among carotenoids may also result in a reduced carotenoid bioavailability. Research into the functional benefits of carotenoids should consider the fact that the bioavailability of beta-carotene in particular is one order of magnitude higher when provided as a pure compound added to foods than when it is present naturally in foods.

Abstract: This update focuses on the bioavailability of dietary calcium for humans. Fundamentals of calcium metabolism, intestinal absorption, urinary excretion and balance are recalled. Dietary factors, especially lactose and other milk components, influencing calcium bioavailability at intestinal and renal levels are reviewed. A critical examination of all the methods used for evaluating calcium bioavailability is made. This includes in vitro assays, classical and isotopic balances, urinary excretion, isotope labeling in the urine, plasma and bones, long term evaluation of bone mineralization and the use of biological bone markers. Importance and advantages of animal models are discussed. The state of the art in the comparative bioavailability of calcium in foods is detailed including a comparison of sources of calcium (dairy products and calcium salts) in human studies and in some animal studies, casein phosphopeptides, proteins, lactose and lactase and their relation with calcium bioavailability (in humans and ...

Abstract: The glucosinolates are a large group of sulphur-containing compounds which occur in all the economically important varieties of Brassica vegetable. Their common structure comprises a β-D-thioglucose group, a sulphonated oxime moiety and a variable side-chain derived from methionine, tryptophan or phenylalanine. When the plant tissue is damaged the glucosinolates are hydrolysed by the endogenous enzyme ‘myrosinase’ (thioglucoside glycohydrolase EC 3:2:3:1), to release a range of breakdown products including the bitter, biologically active isothiocyanates. Although these compounds exert antinutritional effects in animals there is also substantial evidence that they are the principal source of anticarcinogenic activity in Brassica vegetables, and this provides a strong motive for the manipulation of glucosinolate levels in vegetables for human consumption. This review provides an overview of the evidence for a beneficial role for glucosinolates in human health, and describes the current state of knowledge regarding the genetics and biosynthesis of glucosinolates, their chemical analysis, their behaviour during cooking and processing, and their bioavailability to humans. As the genetic basis of glucosinolate biosynthesis becomes more apparent, and tools for marker-assisted plant breeding become more available, the selective breeding of horticultural brassicas with different levels and types of glucosinolates, whether by conventional means or genetic manipulation, is becoming a practical possibility. However before this strategy becomes commercially viable, the health benefits of glucosinolates for human beings must be unequivocally established. © 2000 Society of Chemical Industry

Abstract: Transport by ATP-dependent efflux pumps such as P-glycoprotein is an increasingly recognized determinant of drug disposition P-glycoprotein does not only contribute to multidrug resistance (MDR) in tumor cells, it is also expressed in normal tissues with excretory function such as liver, kidney and intestine Apical expression of P-glycoprotein in such tissues results in reduced drug absorption from the gastrointestinal tract and enhanced drug elimination into bile and urine Moreover, expression of P-glycoprotein in the endothelial cells of the blood-brain barrier prevents entry of certain drugs into the central nervous system Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, cyclosporine and HIV-1 protease inhibitors Drug administration to P-glycoprotein knock-out and control mice provided data on the importance of P-glycoprotein for absorption after oral administration and penetration through the blood-brain barrier Moreover, P-glycoprotein knock-out mice were used to identify inhibition of P-glycoprotein-mediated transport as a mechanism for drug interactions such as the digoxin-quinidine interaction Studies in humans indicate a particular importance of intestinal P-glycoprotein for bioavailability of the immunosuppressant cyclosporine Moreover, induction of intestinal P-glycoprotein by rifampin has now been identified as the major underlying mechanism of reduced digoxin plasma concentrations during concomitant rifampin therapy In summary, P-glycoprotein functions as a defense mechanism, which determines bioavailability and CNS concentrations of drugs Modification of P-glycoprotein function is an important underlying mechanism of drug interactions in humans However, disposition of a drug and its metabolites frequently is not only determined by P-glycoprotein, but also by drug-metabolizing enzymes and possibly by drug transporters other than P-glycoprotein [eg members of the MRP family (MRP = multidrug resistance-associated proteins)]

Abstract: The flavonoid quercetin is an antioxidant which occurs in foods mainly as glycosides. The sugar moiety in quercetin glycosides affects their bioavailability in humans. Quercetin-3-rutinoside is an important form of quercetin in foods, but its bioavailability in humans is only 20% of that of quercetin-4'-glucoside. Quercetin-3-rutinoside can be transformed into quercetin-3-glucoside by splitting off a rhamnose molecule. We studied whether this 3-glucoside has the same high bioavailability as the quercetin-4'-glucoside. To that end we fed five healthy men and four healthy women (19-57 y) a single dose of 325 micromol of pure quercetin-3-glucoside and a single dose of 331 micromol of pure quercetin-4'-glucoside and followed the plasma quercetin concentrations. The bioavailability was the same for both quercetin glucosides. The mean peak plasma concentration of quercetin was 5.0+/-1.0 micromol/L (+/-SE) after subjects had ingested quercetin-3-glucoside and 4.5+/-0.7 micromol/L after quercetin-4'-glucoside consumption. Peak concentration was reached 37 +/-12 min after ingestion of quercetin-3-glucoside and 27+/-5 min after quercetin-4'-glucoside. Half-life of elimination of quercetin from blood was 18.5+/-0.8 h after ingestion of quercetin-3-glucoside and 17.7+/-0.9 h after quercetin-4'-glucoside. We conclude that quercetin glucosides are rapidly absorbed in humans, irrespective of the position of the glucose moiety. Conversion of quercetin glycosides into glucosides is a promising strategy to enhance bioavailability of quercetin from foods.

Abstract: Tomatoes are the main dietary source of lycopene, and the bioavailability of lycopene from tomato paste is higher than that from fresh tomatoes. We investigated systematically the effect of mechanical homogenization and heating on the bioavailability of carotenoids from canned tomatoes. Further, we compared the carotenoid response in triglyceride-rich lipoproteins (TRL) after single consumption with the change in fasting plasma carotenoid concentrations after 4 d of daily consumption. In a split plot design, 17 men and women consumed tomatoes which had received minimal additional heating and 16 others consumed extensively additionally heated tomatoes (1 h at 100 degrees C). These tomatoes were not, mildly or severely homogenized. The tomato products were consumed daily (ca. 22 mg/d lycopene) for 4 d. Eleven participants provided postprandial blood samples on the d 1 and all gave fasting blood samples on d 1 and 4. Homogenization enhanced the lycopene response significantly (P<0.05) both in TRL [mean areas under the curves: 54.9, 72.0 and 88.7 nmol. h/L (SE 11.0) for not, mildly and severely homogenized tomatoes, respectively] and in plasma [mean changes: 0.19, 0.22 and 0.23 micromol/L (SE 0.009), respectively]. Additional heating also tended to enhance the lycopene responses in TRL (P = 0.14) and plasma (P = 0.17). Similar effects to those for lycopene were found for beta-carotene. We conclude that the intactness of the cellular matrix of tomatoes determines the bioavailability of carotenoids and that matrix disruption by mechanical homogenization and/or heat treatment enhances the bioavailability. The carotenoid response in plasma after 4 d intervention can be used to compare the bioavailability of carotenoids from different foods.

Abstract: The absolute bioavailability of oral melatonin tablets was studied in 12 normal healthy volunteers. Subjects were administered, in a randomized crossover fashion, melatonin 2 mg intravenously and 2 and 4 mg orally. Blood was sampled over approximately eight (estimated) half-lives. Both the 2 and the 4 mg oral dosages showed an absolute bioavailability of approximately 15%. No difference in serum half-life was seen in any of the study phases. Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first-pass metabolism, or a combination of both. Further studies examining larger doses, in an attempt to saturate first-pass metabolism if it occurs, may be warranted.

Abstract: Various compounds of the artemisinin family are currently used for the treatment of patients with malaria worldwide. They are characterised by a short half-life and feature the most rapidly acting antimalarial drugs to date. They are increasingly being used, often in combination with other drugs, although our knowledge of their main pharmacological features (including their absorption, distribution, metabolism and excretion) is still incomplete. Such data are particularly important in the case of combinations. Artemisinin derivatives are converted primarily, but to different extents, to the bioactive metabolite artenimol after either parenteral or gastrointestinal administration. The rate of conversion is lowest for artelinic acid (designed to protect the molecule against metabolism) and highest for the water-soluble artesunate. The absolute and relative bioavailability of these compounds has been established in animals, but not in humans, with the exception of artesunate. Oral bioavailability in animals ranges, approximately, between 19 and 35%. A first-pass effect is highly probably for all compounds when administered orally. Artemisinin compounds bind selectively to malaria-infected erythrocytes to yet unidentified targets. They also bind modestly to human plasma proteins, ranging from 43% for artenimol to 81.5% for artelinic acid. Their mode of action is still not completely understood, although different theories have been proposed. The lipid-soluble artemether and artemotil are released slowly when administered intramuscularly because of the 'depot' effect related to the oil formulation. Understanding the pharmacokinetic profile of these 2 drugs helps us to explain the characteristics of the toxicity and neurotoxicity. The water-soluble artesunate is rapidly converted to artenimol at rates that vary with the route of administration, but the processes need to be characterised further, including the relative contribution of pH and enzymes in tissues, blood and liver. This paper intends to summarise contemporary knowledge of the pharmacokinetics of this class of compounds and highlight areas that need further research.

Abstract: Herbal medicinal products containing natural volatiles are used in the treatment of gastrointestinal diseases, pain, colds and bronchitis. Many pharmacological studies report a wide variety of in vitro effects, with anti-inflammatory and antimicrobial activities investigated most frequently. In comparison, relatively few studies on the bioavailability and pharmacokinetics have been carried out. Thus, the relevance of the in vitro activity to the therapeutic effects found in individual studies or documented in textbooks of phytotherapy is still not established. Further studies with essential oils and their single compounds providing supporting evidence of efficacy and demonstrating systemic availability are necessary. Such data could also be important in the context of safety.

Abstract: The absorption characteristics and oral bioavailability of three tea catechins, namely (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG), were assessed in this study. Male Sprague Dawley rats (210-230 g) received either an intravenous (i.v. 50 mg/kg) or oral (5000 mg/kg) dose of decaffeinated catechin-fraction containing EC (5%), EGCG (50%), and ECG (13%). Concentrations of the compounds in plasma, urine, and feces were measured using HPLC. A non-compartmental approach was employed for pharmacokinetic analysis. Results indicated that maximum plasma concentrations for the catechins (15-112 micrograms/ml) were achieved at 2 h post-oral dosing and the apparent volume of distribution (Vd/F) ranged from 30 to 63 l/kg. Absolute bioavailability (F) of EC, EGCG, and ECG was assessed to be 0.39, 0.14, and 0.06, respectively. Estimates of terminal elimination half-life (t1/2, lambda z) of the catechins after oral dosing were 451-479 min and were 1.4-10 fold longer than those observed for the i.v. dosing. The discrepancy in terminal elimination and low rate and extent of absorption indicated the possibility of flip-flop kinetics. Respective urinary recoveries were 0.17-4.72% and 2.11-14.2% after oral and i.v. dosing. In conclusion, the low systemic availability of tea catechins observed could be a result of slow absorption, high first pass effect, and wide tissue distribution.

Abstract: Background A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine. Methods Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models. Results The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P Conclusions The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.

Abstract: This study was conducted to determine the bioavailability of iron amino acid chelate (ferrochel) added to fortify breads prepared from either precooked corn flour or white wheat flour + cheese and margarine compared with the same basal breakfast enriched with either ferrous sulfate or iron-EDTA. The inhibitory effect of phytate and polyphenols on iron absorption from ferrochel was also tested. A total of 74 subjects were studied in five experiments. Iron absorption from ferrochel was about twice the absorption from ferrous sulfate (P: < 0.05). When ferrous sulfate and ferrochel were administered together or in different meals, absorption from ferrochel was about twice the absorption from ferrous sulfate (P: < 0.05). Polyphenols present in coffee and tea inhibited iron absorption in a dose-dependent manner. American-type coffee did not modify iron absorption significantly, whereas both espresso-type coffee and tea reduced iron absorption from ferrochel by 50% (P: < 0. 05). Ferrochel partially prevented the inhibitory effect of phytates. Because of its high solubility in aqueous solutions even at pH 6, its low interactions with food and high absorption, ferrochel is a suitable compound for food fortification.

Abstract: Purpose. The purpose of this investigation was to develop aquantitative structure-bioavailability relationship (QSBR) model for drugdiscovery and development.

Abstract: Previous studies in mice with disrupted mdr1a P-glycoprotein genes have shown that the oral bioavailability of paclitaxel is very low because of the presence of this drug-transporting protein in the intestinal wall. Additional studies with cyclosporin A have shown that this P-glycoprotein-inhibiting agent is able to increase the bioavailability of paclitaxel in mouse models and in patients. However, the potential immune-suppressive side effects of cyclosporin A renders this compound less suitable for chronic use in cancer patients. In this paper we present the results obtained with GF120918, an experimental P-glycoprotein inhibitor, on the oral bioavailability of paclitaxel in both wild-type and mdr1ab knockout mice. GF120918 (25 mg/kg) was administered p.o. by gavage 15 min or 2 h before oral or i.v. dosing of paclitaxel, respectively. Paclitaxel plasma levels were quantified by high-performance liquid chromatography. GF120918 increased the plasma values for areas under the concentration-time curve of oral paclitaxel in wild-type mice by 6.6-fold from 408 to 2701 ng·ml−1·h. Calculated relative to their respective values for area under the concentration-time curve after i.v. administration, GF120918 increased the oral bioavailability of paclitaxel in wild-type mice from 8.5 to 40.2%. The plasma pharmacokinetics of paclitaxel in mdr1ab knockout mice was not altered by GF120918, whereas the pharmacokinetics of paclitaxel in wild-type mice receiving GF120918 became comparable with mdr1ab knockout mice. This result indicates that GF120918 at this dose-level selectively and completely blocks P-glycoprotein in the intestines and does not notably interfere in the elimination of paclitaxel by metabolism or other transporters. On the basis of this result, GF120918 has been selected for additional study in humans.