Abstract: Objectives: To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suit- able for nebulization. Methods: Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs. Results: The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 ± 0.11 µm, favour- able for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained thera- peutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability (compared to intravenous (iv) administration) was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles contain- ing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit.

Abstract: Aim To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2-adrenoceptor agonist, in healthy subjects. Methods Single 2 µg kg−1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration-time data were analysed using linear one-compartment (buccal and peroral data), or two-compartment modelling (intravenous data), or noncompartmental methods (intramuscular data). Results Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12–20%), 82% (73–92%) and 104% (96–112%), respectively. Conclusion Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug.

Abstract: Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (Camellia sinensis), has shown cancer preventive activity in animal models. The bioavailability of EGCG in the most commonly used animal species, mice, is poorly understood. Moreover, the pharmacokinetic parameters of EGCG have not been reported previously in mice. Here we report that after administration of EGCG intravenously at 21.8 mol/kg or intragas- trically at 163.8 mol/kg, the peak plasma levels of EGCG in male CF-1 mice were 2.7 0.7 and 0.28 0.08 mol/L, respectively. EGCG was present mainly (50 -90%) as the glucuronide. The plasma bioavailability of EGCG after intragastric administration was higher than previously reported in rats (26.5 7.5% vs. 1.6 0.6%). The conjugated EGCG displayed a shorter t1/2 (82.8 -211.5 vs 804.9 -1102.3 min) than unconjugated EGCG (P 0.01, Student's t test). EGCG was present in the unconjugated form in the lung, prostate and other tissues at levels of 0.31-3.56 nmol/g after intravenous administration. Although intragastric administration resulted in lower levels in most tissues compared with intravenous administration (e.g., 0.006 0.004 vs. 2.66 1.0 nmol/g in the lung), the levels in the small intestine and colon were high at 45.2 13.5 and 7.86 2.4 nmol/g, respectively. This is the first report of the pharmacokinetic parameters of EGCG in mice. Such information provides a basis for understanding the bioavailability of EGCG in mice and should aid in understanding the cancer preventive activity of EGCG. J. Nutr. 133: 4172- 4177, 2003.

Abstract: L-Carnitine is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for beta-oxidation. Exogenous L-carnitine is used clinically for the treatment of carnitine deficiency disorders and a range of other conditions. In humans, the endogenous carnitine pool, which comprises free L-carnitine and a range of short-, medium- and long-chain esters, is maintained by absorption of L-carnitine from dietary sources, biosynthesis within the body and extensive renal tubular reabsorption from glomerular filtrate. In addition, carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation. The absorption of L-carnitine after oral administration occurs partly via carrier-mediated transport and partly by passive diffusion. After oral doses of 1-6g, the absolute bioavailability is 5-18%. In contrast, the bioavailability of dietary L-carnitine may be as high as 75%. Therefore, pharmacological or supplemental doses of L-carnitine are absorbed less efficiently than the relatively smaller amounts present within a normal diet.L-Carnitine and its short-chain esters do not bind to plasma proteins and, although blood cells contain L-carnitine, the rate of distribution between erythrocytes and plasma is extremely slow in whole blood. After intravenous administration, the initial distribution volume of L-carnitine is typically about 0.2-0.3 L/kg, which corresponds to extracellular fluid volume. There are at least three distinct pharmacokinetic compartments for L-carnitine, with the slowest equilibrating pool comprising skeletal and cardiac muscle.L-Carnitine is eliminated from the body mainly via urinary excretion. Under baseline conditions, the renal clearance of L-carnitine (1-3 mL/min) is substantially less than glomerular filtration rate (GFR), indicating extensive (98-99%) tubular reabsorption. The threshold concentration for tubular reabsorption (above which the fractional reabsorption begins to decline) is about 40-60 micromol/L, which is similar to the endogenous plasma L-carnitine level. Therefore, the renal clearance of L-carnitine increases after exogenous administration, approaching GFR after high intravenous doses. Patients with primary carnitine deficiency display alterations in the renal handling of L-carnitine and/or the transport of the compound into muscle tissue. Similarly, many forms of secondary carnitine deficiency, including some drug-induced disorders, arise from impaired renal tubular reabsorption. Patients with end-stage renal disease undergoing dialysis can develop a secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyser, and L-carnitine has been used for treatment of some patients during long-term haemodialysis. Recent studies have started to shed light on the pharmacokinetics of L-carnitine when used in haemodialysis patients.

Abstract: Bioavailability of contaminants in soils and sediments: processes, tools, and applications , Bioavailability of contaminants in soils and sediments: processes, tools, and applications , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

Abstract: The absorption of drugs via the oral route is a subject of intense and continuous investigation in the pharmaceutical industry since good bioavailability implies that the drug is able to reach the systemic circulation by mouth. Oral dry absorption is affected by both drug properties and the

Abstract: Testing of metal compounds for solubility in artificial fluids has been used for many years to assist determining human health risk from exposure to specific compounds of concern. In lieu of obtaining bioavailability data from samples of urine, blood, or other tissues, these studies measured solubility of compounds in various artificial fluids as a surrogate for bioavailability. In this context, the measurement of metal “bioaccessibility” can be used as an in vitro substitute for measuring metal bioavailability. Bioaccessibility can be defined as a value representing the availability of metal for absorption when dissolved in in vitro surrogates of body fluids or juices. The aim of this study was to measure and compare the bioaccessibility of selected cobalt compounds in artificial human tissue fluids and human serum. A second aim was to initiate studies to experimentally validate an in vitro methodology that would provide a conservative estimate of cobalt bioavailability in the assessment of dose from human exposure to various species of cobalt compounds. This study evaluated the bioaccessibility of cobalt(II) from 11 selected cobalt compounds and an alloy in 2 physical forms in 5 surrogate human tissue fluids and human serum. Four (4) separate extraction times were used up to 72 hours. The effect of variables such as pH, dissolution time, and mass-ion effect on cobalt bioaccessibility were assessed as well. We found that the species of cobalt compound as well as the physico-chemical properties of the surrogate fluids, especially pH, had a major impact on cobalt solubility. Cobalt salts such as cobalt(II) sulfate heptahydrate were highly soluble, whereas cobalt alloys used in medical implants and cobalt aluminate spinels used as pigments, showed minimal dissolution over the period of the assay.

Abstract: 1. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively low levels of systemic absorption. 2. Pharmacokinetic evaluation of drug absorption from the lungs provides an accurate and reproducible method for comparing different inhaler delivery systems, as well as for evaluating bioequivalence of generic drug formulations. 3. The measurement of drug absorption from the lungs may also be applied to assess the effects of inhalation technique on drug delivery in vivo. For example with salbutamol delivered via a large volume spacer, lung bioavailability has been shown to be altered by factors such as the number of actuated puffs, inhalation-actuation delay and washing procedure. 4. Differences in drug delivery to the lungs between dry powder reservoir and pressurised metered-dose aerosol devices translate directly into commensurate differences in clinical efficacy for delivery of both inhaled beta 2-adrenoceptor agonists and corticosteroids. 5. For inhaled corticosteroids, pharmacokinetic evaluation using oral charcoal to obviate alimentary absorption may be applied to quantify the relative gut and lung components of systemic bioavailability. In tandem with information on receptor potency and affinity, drug elimination and distribution, these data may help in part to explain observed differences between different inhaled corticosteroids in terms of their systemic bioactivity profiles. 6. Studies are required to evaluate whether pharmacokinetic evaluation of lung absorption is a suitable way of quantifying delivery of nebulised aminoglycoside antibiotics, as for example in patients with cystic fibrosis. 7. Pharmacokinetic evaluation appears to have an established role in the quantification of drug delivery to the lungs and provides important information which is complimentary to other techniques such as radiolabelled deposition. The next decade of research into pharmacokinetics of established and novel drugs and delivery systems is awaited with keen interest, and will hopefully provide a greater understanding into ways of optimising the benefit-risk ratio for inhaled drugs.

Abstract: Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. They are believed to protect humans from disease and aging. Vitamin C (ascorbic acid), vitamin E (tocopherol), β-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. This article addresses data provided from clinical trials, highlighting the clinical pharmacokinetics of vitamin C, vitamin E, β-carotene, lycopene, lutein, quercetin, rutin, catechins and selenium. The bioavailability of vitamin C is dose-dependent. Saturation of transport occurs with dosages of 200–400) mg/day. Vitamin C is not protein-bound and is eliminated with an elimination half-life (t½) of 10 hours. In Western populations plasma vitamin C concentrations range from 54–91 µmol/L. Serum α- and γ-tocopherol range from 21 µmol/L (North America) to 27 µmol/L (Europe) and from 3.1 µmol/L to 1.5 µmol/L, respectively. α-Tocopherol is the most abundant tocopherol in human tissue. The bioavailability of all-rac-α-tocopherol is estimated to be 50% of R,R,R-α-tocopherol. The hepatic α-tocopherol transfer protein (α-TTP) together with the tocopherol-associated proteins (TAP) are responsbile for the endogenous accumulation of natural α-tocopherol. Elimination of α-tocopherol takes several days with a t½ of 81 and 73 hours for R,R,R-α-tocopherol and all-rac-α-tocopherol, respectively. The t½ of tocotrienols is short, ranging from 3.8–4.4 hours for γ- and α-tocotrienol, respectively. γ-Tocopherol is degraded to 2, 7, 8-trimethyl-2-(β-carboxyl)-6-hyrdoxychroman by the liver prior to renal elimination. Blood serum carotenoids in Western populations range from 0.28–0.52 p,mol/L for β-carotene, from 0.2–0.28 for lutein, and from 0.29–0.60 for lycopene. All-trans-carotenoids have a better bioavailability than the 9-cis-forms. Elimination of carotenoids takes several days with a t½ of 5-7 and 2–3 days for β-carotene and lycopene, respectively. The bioconversion of β-carotene to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl moieties. The t½ ranges from 12–19 hours. The bioavailabillity of catechins is low and they are eliminated with a t½ of 2–4 hours. Catechins are degraded to several γ-valerolactone derivatives and phase II conjugates have also been identified. Only limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been reported to date.

Abstract: The potential for biosolids products to reduce Pb availability in soil was tested on a high Pb urban soil with biosolids from a treatment plant that used different processing technologies. High Fe biosolids compost and high Fe + lime biosolids compost from other treatment plants were also tested. Amendments were added to a Pb-contaminated soil (2000 mg kg -1 Pb) at 100 g kg -1 soil and incubated for 30 d. Reductions in Pb bioavailability were evaluated with both in vivo and in vitro procedures. The in vivo study entailed feeding a mixture of the Pb-contaminated soil and AIN93G Basal Mix to weanling rats. Three variations of an in vitro procedure were performed as well as conventional soil extracts [diethylenetriaminepentaacetic acid (DTPA) and Ca(NO 3 ) 2 ] and sequential extraction. Addition of the high Fe compost reduced the bioavailability of soil Pb (in both in vivo and in vitro studies) by 37 and 43%, respectively. Three of the four compost materials tested reduced Pb bioavailability more than 20%. The rapid in vitro (pH 23) data had the best correlation with the in vivo bone results (R = 0.9). In the sequential extract, changes in partitioning of Pb to Fe and Mn oxide fractions appeared to reflect the changes in in vivo Pb bioavailability. Conventional extracts showed no changes in metal availability. These results indicate that addition of 100 g kg -1 of high Fe and Mn biosolids composts effectively reduced Pb availability in a high Pb urban soil.

Abstract: Lead immobilization in 10 soils contaminated with Pb from different origin was examined using lime (CaCO3), a mix of cyclonic ash and steelshots (CA+ST), and a North Carolina phosphate rock. The immobilization efficacy of the three amendments was evaluated using single (CaCl2solution) and sequential (BCR method) chemical extractions in tandem with a microbiological Pb biosensor (BIOMET), a Pb phytotoxicity test, Pb plant uptake, and a Physiologically Based Extraction Test (PBET) mimicking Pb bioavailability in the human gastro-intestinal tract. The results demonstrated the necessity of using a diverse suite of bioavailability methodology when in situ metal immobilization is assessed. Sequential (BCR) extractions and PBET analysis indicated that PR was the most effective amendment. PR however, proved ineffective in totally preventing Pb phytotoxicity and Pb uptake on all soils tested. On the contrary, CA+ST and lime decreased BIOMET Pb, Pb phytotoxicity, and Pb uptake to a far greater extent than did PR. BIOMET detectable Pb and Pb uptake, however, were strongly related to Pb in soluble or exchangeable soil fractions (i.e., CaCl2 extractable). By combining these fractions with the acid-extractable Pb, accomplished by using acetic acid extractant, the recently developed BCR sequential extraction scheme appeared to have lost some valuable information on judging Pb bioavailability. The data show that different amendments do not behave consistently across different soils with different sources of contamination. Different indices for measuring Pb bioavailability are also not necessarily consistent within particular soil and amendment combinations.

Abstract: Recent investigations suggest that the bioavailability of quercetin depends on the glycoside moiety of the quercetin glycosides present in the diet. In this study, we compared the oral bioavailability of quercetin from quercetin aglycone and two different quercetin glycosides in pigs. Pigs were equipped with permanent catheters in the jugular and portal veins. After consumption of a test meal containing the respective compounds, blood samples were drawn repeatedly over a period of 24 h and analyzed by HPLC. In a first set of experiments, pigs received a single oral dose of 148 micromol/kg body (equivalent to 50 mg/kg) provided as quercetin aglycone, quercetin-3-O-glucoside (Q3G) or quercetin-3-O-glucorhamnoside (rutin) as part of their diet. The main metabolite in plasma was always conjugated quercetin, whereas free quercetin was not detected in either the jugular or the portal blood. For Q3G and rutin, the relative total bioavailability of quercetin (i.e., conjugated quercetin and conjugated methylethers of quercetin) was 148% (P = 0.07) and 23% (P < 0.05), respectively, compared with quercetin aglycone. In another experiment with a dose of 29.6 micro mol/kg (equivalent to 10 mg/kg), the relative total bioavailability of Q3G was 167% compared with the aglycone (P < 0.05). Bioavailability of Q3G was significantly higher when the test meal was ground beef rather than the standard ration. Our results indicate that the bioavailability of quercetin from quercetin glycosides is determined by a complex interdependence between the chemical form of the flavonols and dietary factors.

Abstract: Purpose. To explore the use of cyclodextrins (CD) to form inclusion complexes with β-lapachone (β-lap) to overcome solubility and bioavailability problems previously noted with this drug.

Abstract: Grapefruit juice produces mechanism-based inhibition of intestinal drug metabolism when consumed in normal quantities. This can produce clinically important increases in oral drug bioavailability when coadministered with substrates of cytochrome p450 3A4 (CYP3A4) that undergo high presystemic metabolism. Furanocoumarins such as bergamottin and 6',7'-dihydroxybergamottin have been identified as probable active constituents. Grapefruit juice may also inhibit intestinal P-glycoprotein-mediated efflux transport of drugs such as cyclosporine to increase its oral bioavailability. However, grapefruit juice does not enhance the absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it has high inherent oral bioavailability. Grapefruit and other fruit juices have recently been shown to be potent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs). These juices were also found to decrease the absorption of the nonmetabolized OATP substrate, fexofenadine. Taken together, the data support inhibition of intestinal uptake transporters by fruit juices to decrease drug bioavailability. This would represent a new mechanism for food-drug interactions. These findings with grapefruit and other fruit juices continue to enhance our understanding of the complex nature of food-drug interactions, and their possible influence on the clinical effects of medications.

Abstract: Purpose. In an attempt to improve the oral bioavailability of paclitaxel, a novel P-glycoprotein inhibitor, KR30031, which is verapamil analog with fewer cardiovascular effects, was coadministered with paclitaxel, and to elucidate other possible causes of the low oral bioavailability of paclitaxel, an inhibitor of hepatic metabolism, ketoconazole, was also coadministered with paclitaxel.

Abstract: Seven randomised comparative studies were conducted in healthy volunteers to compare the pharmacokinetic and pharmacodynamic profiles of selegiline hydrochloride in a new formulation designed for buccal absorption "Zydis Selegiline" (1.25-10 mg) with conventional selegiline hydrochloride tablets "conventional selegiline tablets" (10 mg). A total of 156 healthy volunteers participated in these studies. Plasma concentrations of selegiline and its primary metabolites, N-desmethylselegiline (DMS), l-amphetamine (AMT), and l-methamphetamine (MET) were measured using Gas Chromatography Mass Spectrometry (GCMS) and gas liquid chromatography (GLC) assays. Inhibition of monoamine-oxidase type B (MAO-B) and monoamine oxidase type A (MAO-A) activity was determined by measurement of as beta-phenylethylamine (PEA) by GCMS and 5-hydroxyindoleacetic acid (5-HIAA) by High Performance Liquid Chromatography (HPLC) assays. Almost a third (2.96 mg) of a 10 mg selegiline dose in Zydis Selegiline was absorbed pre-gastrically (predominantly buccally) within 1 minute. Mean [SD] area-under-the curve (AUC(0- infinity)) values following Zydis Selegiline 10 mg (5.85 [7.31] ng.h/mL) were approximately five times higher than those following conventional selegiline tablets 10 mg (1.16 [1.05] ng.h/mL). In contrast, plasma concentrations of metabolites were significantly ( p<0.001) lower following Zydis Selegiline 10 mg than following conventional selegiline tablets 10 mg. Plasma concentrations of selegiline and its metabolites increased in a dose-dependent manner over the dose-range Zydis Selegiline 1.25-5 mg. Bioavailability was determined using AUC and peak plasma concentrations (C(max)). The C(max) of selegiline was similar following administration of Zydis Selegiline 1.25 mg (1.52 ng/mL) or conventional selegiline tablets 10 mg (1.14 mg/mL). The range of values for AUC(0- infinity) and C(max) following Zydis Selegiline 1.25 mg were entirely contained within the range following conventional selegiline tablets 10 mg, with a much higher variability of plasma selegiline concentrations occurring after conventional selegiline tablets than after Zydis Selegiline. As expected, peak plasma concentrations for DMS, AMT and MET were consistently lower after Zydis Selegiline 1.25 mg (1.19, 0.34, 0.93 ng/ml, respectively) than after conventional selegiline tablets 10 mg (18.37, 3.60, 12.92 ng/ml, respectively). A significant (r=0.0001) correlation between daily PEA excretion (a measure of brain MAO-B inhibition) and the log-transformed AUC((0-t)) for selegiline was demonstrated. Mean daily PEA excretion was similar following Zydis Selegiline 1.25 mg and conventional selegiline tablets 10 mg (13.0 microg versus 17.6 microg). In contrast, there was no correlation between PEA excretion and selegiline metabolites, indicating that selegiline metabolites do not significantly inhibit MAO-B. Urinary excretion of 5-HIAA (used as a marker for MAO-A inhibition) was unrelated to plasma concentrations of selegiline or DMS following single or repeat dosing of Zydis Selegiline 1.25 mg or conventional selegiline tablets 10 mg. However, comparison of treatment groups revealed a significantly lower excretion of 5-HIAA in the conventional selegiline tablets 10 mg group than in the Zydis Selegiline 1.25 mg group after repeated administration over 13 days. In summary, by reducing the opportunity for first-pass metabolism, the absorption of selegiline from Zydis Selegiline was more efficient and less variable than from conventional selegiline tablets. Compared with conventional selegiline tablets 10 mg, Zydis Selegiline 1.25 mg yielded similar plasma concentrations of selegiline and degree of MAO-B inhibition, but markedly reduced concentrations of the principal metabolites. Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25 mg, which is associated with lower concentrations of potentially harmful metabolites, could offer a safer and more predictable treatment in the management of patients with Parkinson's disease.

Abstract: Bioavailability of pesticides sorbed to soils is an important determinant of their environmental fate and impact. Mineralization of sorbed atrazine was studied in soil and clay slurries, and a desorption-biodegradation-mineralization (DBM) model was developed to quantitatively evaluate the bioavailability of sorbed atrazine. Three atrazine-degrading bacteria that utilized atrazine as a sole N source (Pseudomonas sp. strain ADP, Agrobacterium radiobacter strain J14a, and Ralstonia sp. strain M91-3) were used in the bioavailability assays. Assays involved establishing sorption equilibrium in sterile soil slurries, inoculating the system with organisms, and measuring the CO(2) production over time. Sorption and desorption isotherm analyses were performed to evaluate distribution coefficients and desorption parameters, which consisted of three desorption site fractions and desorption rate coefficients. Atrazine sorption isotherms were linear for mineral and organic soils but displayed some nonlinearity for K-saturated montmorillonite. The desorption profiles were well described by the three-site desorption model. In many instances, the mineralization of atrazine was accurately predicted by the DBM model, which accounts for the extents and rates of sorption/desorption processes and assumes biodegradation of liquid-phase, but not sorbed, atrazine. However, for the Houghton muck soil, which manifested the highest sorbed atrazine concentrations, enhanced mineralization rates, i.e., greater than those expected on the basis of aqueous-phase atrazine concentration, were observed. Even the assumption of instantaneous desorption could not account for the elevated rates. A plausible explanation for enhanced bioavailability is that bacteria access the localized regions where atrazine is sorbed and that the concentrations found support higher mineralization rates than predicted on the basis of aqueous-phase concentrations. Characteristics of high sorbed-phase concentration, chemotaxis, and attachment of cells to soil particles seem to contribute to the bioavailability of soil-sorbed atrazine.