Arsenic trioxide absorption and excretion in industry

1. A study of 24 smelter workers routinely exposed to arsenic trioxide was conducted to evaluate some characteristics of its absorption and excretion. A statistically significant correlation was found between airborne arsenic trioxide concentrations below 300 mug/m3 and urinary arsenic values below 500 mug/liter. These men wore personal monitors for five consecutive work days and were determined to have been exposed to average airborne arsenic concentrations of 53 mug/m3 (70 mug/m3 of arsenic trioxide) which increased their urinary arsenic values from 152 mug/liter to 200 mug/liter (an average gain on 32%). 2. The background average urinary arsenic value for adult males not exposed to arsenic trioxide in industry was determined to be 52.6 mug/liter for 204 men during preemployment examinations. 3. After removal from industrial arsenic trioxide exposure, the rate of fall in urinary arsenic values varies with the magnitude of the urinary arsenic level. An initial decrease of 9.5% per day was measured for workers having urinary arsenic values below 200 mug/liter. The initial decrease is about 21% per day for workers with urinary arsenic values over 600 mug/liter. 4. It was determined that arsenic in seafood can alter, in a dramatic fashion, the urinary arsenic values determined for smelter workers within 24 hours following consumption. It is recommended, therefore, that the absorption of arsenic trioxide due to industrial exposure is best evaluated from urine samples collected at least two days after seafood has been eaten.     

Characteristics of delayed excretion of flavonoids in human urine after administration of Shosaiko-to, a herbal medicine

There has been little explanation of herbal medicines by modern medical sciences, including pharmacokinetics, whereas physicians follow empirical indications written in classical literature. Recent reports of herb-induced adverse reactions compelled us to proceed the investigation of a herbal medicine Shosaiko-to (TJ-9) from a pharmacokinetic point of view. To five healthy volunteers, a single 5 g dose of TJ-9, consisting of 7 herbs, was administered. We conducted HPLC analysis of the timed-urine specimens to disclose the type and amount of compounds excreted. Excretion rate-time curves were analyzed individually. Four flavonoids, liquiritigenin, baicalein, wogonin and oroxylin A, were found both in the urine and TJ-9. The glycosides in TJ-9 were absorbed after microflora hydrolysis. Davidigenin, which was not found in TJ-9, was an intestinal metabolite of liquiritigenin. Also, two flavanones, S-dihydrowogonin and S-dihydrooroxylin A, were identified as the metabolites of wogonin and oroxylin A, respectively. Excretion rate-time curves of the flavonoids were divided into three types of structure-dependent absorption, i.e. (1) the fast absorption of herbal-origin aglycons, (2) the moderately-delayed absorption of aglycons derived from herbal glycosides, and (3) markedly-delayed absorption after the molecular transformation of herbal compounds. Individual excretion profiles seemed to depend on microflora activities. Two types of flavanones, S-dihydrowogonin and S-dihydrooroxylin A, were found in a half of the volunteers, suggesting there might be two kinds of volunteers, namely, rapid and poor metabolizers of flavonoids.     

Molecular and cell biological analyses for intestinal absorption and renal excretion of drugs

Intestinal absorption and renal tubular secretion are transport processes determining the availability and the disposition of drugs in the body. In this review, our studies on the molecular and cell biological analyses of intestinal absorption and renal secretion of drugs are described. We evaluated the transepithelial transport and the cellular accumulation of peptide-like drugs such as beta-lactam antibiotics and bestatin (a dipeptide-like antineoplastic agent) in the human adenocarcinoma colon cell line, Caco-2, as an in vitro model for studying absorption mechanisms of these drugs. We have found that the transcellular transport of these peptide-like drugs is mediated by both the apically- and basolaterally-localized peptide transporters. To characterize molecular aspects of absorption of the peptide-like drugs, we studied cDNA cloning of H+/peptide cotransporters, PEPT1 and PEPT2, expressed in rats. The rat PEPT1 has been shown to mediate the H- coupled uphill transport of beta-lactam antibiotics across the brush-border membranes of the intestinal and renal epithelia. The rat PEPT2 is expressed predominantly in the kidney, but not in the intestine, mediating tubular reabsorption of the peptide-like drugs. We examined the transcellular transport of organic cations across monolayers of the kidney epithelial cell line, LLC-PK1. We have found that LLC-PK1 cells possess the H+/organic cation antiporter and the membrane potential-sensitive organic cation transporter in the apical and basolateral membranes, respectively, thereby tetraethylammonium (TEA) being transported unidirectionally from the basolateral to the apical side of the monolayers. We have isolated a cDNA encoding a rat kidney-specific organic cation transporter, OCT 2, which transports TEA in a H(+)-gradient independent manner, suggesting that OCT2 is localized to the basolateral membranes of renal tubular cells. In addition, a cDNA encoding a novel rat organic anion transporter, OAT-K1, has been cloned. OAT-K1 is expressed exclusively in the renal proximal tubules, and mediates the transport of methotrexate. Analyses of the molecular and cell biological mechanisms for drug absorption and secretion will provide information for the understanding of organ specific drug transport systems and for the development of drug design and/or drug delivery system.     

Absorption and excretion of conjugated flavonols, including quercetin-4''-O-beta-glucoside and isorhamnetin-4''-O-beta-glucoside by human volunteers after the consumption of onions

The evolution of clinical practice protocols is described within the context of its origins in utilization review and utilization management. Physician concerns and barriers to implementation, as well as the role of the Agency for Health Care Policy and Research (AHCPR) are discussed. An example of competing guidelines from the AHCPR and the American Psychiatric Association is described in detail. The available literature on cost savings related to utilization management and clinical guidelines is reviewed and summarized. With over 1,800 medical practice guidelines catalogued, practice protocols have become ubiquitous and continued research into their cost and impact on quality are needed.     

Biliary lipid excretion after hepatic portoenterostomy

A kinetic approach to sequence analysis is presented. A polymer chain composed of a small number of monomer types is degraded continuously with degradation proceeding in only one direction of the chain. Ordinarily, the direct determination of the sequence from the amount of degraded monomers is hampered by the rapid loss of reaction synchrony. However, it is shown, that if the monomers can be measured reasonably accurately, one can solve a system of linear equations with the unknowns giving the positions of the monomers in the chain, and the syn chrony loss due to the stochastic nature of the degradation process can be accounted for. Model calculations are presented.     

Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables

Isothiocyanates and their naturally occurring glucosinolate precursors are widely consumed as part of a diet rich in cruciferous vegetables. When plant cells are damaged, glucosinolates are released and converted to isothiocyanates by the enzyme myrosinase. Many isothiocyanates inhibit the neoplastic effects of various carcinogens at a number of organ sites. Consequently, these agents are attracting attention as potential chemoprotectors against cancer. As a prerequisite to understanding the mechanism of the protective effects of these compounds, which is thought to involve the modulation of carcinogen metabolism by the induction of phase 2 detoxication enzymes and the inhibition of phase 1 carcinogen-activating enzymes, we examined the fate of ingested isothiocyanates and glucosinolates in humans. Recently developed novel methods for quantifying isothiocyanates (and glucosinolates after their quantitative conversion to isothiocyanates by purified myrosinase) and their urinary metabolites (largely dithiocarbamates) have made possible a detailed examination of the fates of isothiocyanates and glucosinolates of dietary crucifers. In a series of studies in normal volunteers, we made these findings. First, in nonsmokers, urinary dithiocarbamates were detected only after the consumption of cruciferous vegetables and condiments rich in isothiocyanates and/or glucosinolates. In sharp contrast, the consumption of noncrucifers (corn, tomatoes, green beans, and carrots) did not lead to the excretion of dithiocarbamates. Moreover, the quantities of dithiocarbamates excreted were related to the glucosinolate/isothiocyanate profiles of the cruciferous vegetables administered (kale, broccoli, green cabbage, and turnip roots). Second, eating prepared horseradish containing graded doses of isothiocyanates (12.3-74 micromol; mostly allyl isothiocyanate) led to a rapid excretion of proportionate amounts (42-44%) of urinary dithiocarbamates with first-order kinetics. The ingestion of broccoli in which myrosinase had been heat-inactivated also led to proportionate but low (10-20%) recoveries of urinary dithiocarbamates. Broccoli samples subsequently treated with myrosinase to produce the cognate isothiocyanates were much more completely (47%) converted to dithiocarbamates. Finally, when bowel microflora were reduced by mechanical cleansing and antibiotics, the conversion of glucosinolates became negligible. These results establish that humans convert substantial amounts of isothiocyanates and glucosinolates to urinary dithiocarbamates that can be easily quantified, thus paving the way for meaningful studies of phase 2 enzyme induction in humans.     

Plasma and blood lead concentrations, lead absorption, and lead excretion in nonhuman primates

The effects of pH, temperature, block of energy production, calcium/calmodulin, protein phosphorylation, and cytoskeleton-disrupting agents (cytochalasin D, nocodazole) on the integrity of the membrane skeleton were studied in polarized MDCK cells. The intracellular distributions of alpha-fodrin, actin, and ankyrin were monitored by immunofluorescence microscopy. The membrane skeleton, once assembled, seemed to be quite stable; the only factors releasing alpha-fodrin from the lateral walls were the acidification of the cytoplasm and the depletion of extracellular calcium ions. Upon cellular acidification, some actin was also released from its normal location along the lateral walls and was seen in colocalization with alpha-fodrin in the cytoplasm, whereas ankyrin remained associated with the lateral walls. No accumulation of plasma membrane lipids was observed in the cytoplasm of acidified cells, as visualized by TMA-DPH. These results suggest that the linkages between the fodrin-actin complex and its membrane association sites are broken upon acidification. The pH-induced change in alpha-fodrin localization was reversible upon restoring the normal pH. Reassembly of the membrane skeleton, however, required temperatures above +20 degrees C, normal energy production, proper cell-cell contacts, and polymerized actin. Release of alpha-fodrin from the lateral walls to the cytoplasm was also observed upon depletion of extracellular calcium ions. This change was accompanied by the disruption of cell-cell contacts, supporting the role of proper cell-cell contacts in the maintenance of the membrane skeleton polarity. These results suggest that local alterations of the cytoplasmic pH and calcium ion concentration may be important in regulating the integrity of the membrane skeleton.     

Nicotine absorption after pulmonary instillation

Levels of nicotine in plasma were determined by gas chromatography in eight mongrel dogs after instillation of 0.5 mg of nicotine in 100 microL of normal saline at three levels of the tracheobronchial tree: the trachea, a subsegmental bronchus of the right middle lobe, and a subpleural location of the right middle lobe ("distal"). An equivalent dose was given intravenously (iv). Peak of nicotine concentrations in plasma were significantly lower after instillation at the trachea (11.5 +/- 4.4 ng/mL) and the subsegmental bronchus (18.2 +/- 5.0 ng/mL) than after an iv dose (30.3 +/- 10.7 ng/mL); p < 0.05 for each comparison. In addition, the peak concentration after instillation at the trachea was significantly lower than that after instillation at the distal site (22.1 +/- 6.2 ng/mL, p < 0.05). Time to peak concentration was significantly longer after tracheal instillation (5.3 +/- 3.0 min) than after subsegmental instillation (2.0 +/- 0.0 min) or iv infusion (2.0 +/- 0.0 min); p < 0.05 for each comparison. Total drug absorbed, half-life, and clearance were equivalent from all four sites. This study demonstrated that quantitative absorption of nicotine from the described lung sites is equivalent to that after an iv dose, with slower absorption and lower peak concentrations from the tracheal site.     

Biliary cholesterol excretion: a novel mechanism that regulates dietary cholesterol absorption

The regulation of dietary cholesterol absorption was examined in C57BL/6 and transgenic mice with liver overexpression of the scavenger receptor BI (SR-BI Tg). In C57BL/6 animals, feeding 0.02 to 1% (wt/wt) dietary cholesterol resulted in a dose-dependent decrease in the percentage of dietary cholesterol absorbed. A plot of total daily mass of dietary cholesterol absorbed versus the percentage by weight of cholesterol in the diet yielded a curve suggesting a saturable process with a Km of 0.4% (wt/wt) and a Vmax of 0.65 mg cholesterol/g body weight per day. Dietary cholesterol suppressed hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity, stimulated cholesterol 7alpha-hydroxylase activity, and enhanced fecal excretion of bile acids, but none of these changes correlated with the percentage of dietary cholesterol absorption. Dietary cholesterol also caused an increase in biliary cholesterol concentration, and in this case the concentration of biliary cholesterol was strongly and inversely correlated with the percentage dietary cholesterol absorption (r = -0.63, P < 0.0001). Biliary cholesterol concentration was also directly correlated with daily cholesterol intake, dietary cholesterol mass absorption, and liver cholesterol ester content. Transgene-induced overexpression of SR-BI resulted in a stimulation of excretion of cholesterol into the bile and suppressed percentage dietary cholesterol absorption. Furthermore, biliary cholesterol levels in SR-BI Tg mice were strongly and inversely correlated with the percentage of dietary cholesterol absorbed (r = -0.99, P < 0.0008). In summary, these results suggest that the excretion of cholesterol into the bile plays an important role in regulating the percentage absorption of dietary cholesterol.     

Human urinary fluoride excretion at various ages (author's transl)

3 groups, each consisting of 5 subjects in the following age ranges (A 4 to 6 years, B 25 to 45 years, C 60 to 70 years) were given fluoride in the form of a single dose of 6 mg. Fluoride excretion in the urine was subsequently investigated over a period of 24 hours. In a second experiment a daily dose of 6 mg of F- was given to the 3 groups over a period of 10 days. The urinary excretion was determined in 24-hour urine samples. The results are presented in two figures. 1. A time drift in urinary fluoride excretion in the direction of delayed fluoride metabolism was seen in group C subjects. 2. A periodic increase in the urinary fluoride values was also seen in these elderly subjects, indicative of an altered regulatory mechanism.     

Failure of absorption of gabapentin after rectal administration

PURPOSE: We wished to determine the extent of absorption of gabapentin (GBP) after rectal administration to children on maintenance therapy. METHODS: Two children scheduled for extensive surgery received GBP rectally and orally. A pharmacokinetic profile was derived after each route of administration. RESULTS: Serum GBP levels after rectal administration decreased at a rate similar to their rate of decrease after oral administration. However, GBP concentrations were much lower after rectal administration; therefore, we concluded that the aqueous solution was poorly absorbed rectally. The GBP half-life (t1/2) for the 2 children after oral doses were 4.2 and 4.8 h. CONCLUSIONS: Rectal administration of GBP is not satisfactory when oral administration is interrupted. When oral GBP therapy is temporarily discontinued, clinicians should consider administration of alternative antiepileptic drugs (AEDs) that can be administered parenterally or rectally.     

Fractional absorption of L-carnitine after oral administration in rats: evaluation of absorption site and dose dependency

We evaluated the fractional absorption of L-carnitine, a gamma-amino acid essential cofactor for the transfer of long-chain fatty acids, in rats in vivo after oral administration to determine its absorption behavior. At both low (0.05 micromol/rat) and high (100 micromol/rat) doses, L-carnitine was recovered only from the region of the cecum and below at 10 h after administration. During a major shift in distribution from cecum at 10 h to feces at 24 h, there was no significant change in the total recovery at each dose, suggesting that L-carnitine absorption is negligible in the cecum and the large intestine (colon and rectum). However, the recovery of L-carnitine was incomplete and the fraction recovered was larger at the high dose than at the low dose. The fractions absorbed were estimated to be 96.7 and 33.0% for the low and high doses, respectively, as these were the fractions that disappeared from the gastrointestinal tract. These values were comparable with 100 and 42%, respectively, of bioavailability values by the pharmacokinetic analysis of plasma concentration data in our preceding study [Matsuda et al., Biopharmaceutics & Drug Disposition, in press]. These results suggest that L-carnitine is significantly absorbed only in the small intestine, without undergoing first-pass degradation, and in a dose-dependent manner presumably due to the involvement of saturable transport by L-carnitine carriers. Consistent with the suggestions in vivo, L-carnitine absorption in the closed intestinal loop in situ was concentration-dependent in the small intestine but not in the large intestine, and the apparent membrane permeability in the large intestine was smaller by an order of magnitude than that of passive transport in the small intestine. These findings support our preceding kinetic modeling strategy assuming the small intestine to be the sole absorption site, and should be of help in guiding studies on development of more efficient oral L-carnitine delivery strategies.     

Mortality and light to moderate alcohol consumption after myocardial infarction

BACKGROUND: Although heavy alcohol consumption increases total mortality, light to moderate consumption decreases cardiovascular and all-cause mortality in apparently healthy people. Since data are sparse on the relation of light to moderate alcohol intake to mortality in patients with previous myocardial infarction, we did a prospective study of mortality in men. METHOD: Of 90,150 men in the Physicians' Health Study enrollment cohort who provided information on alcohol intake and who had no history of cancer, stroke, or liver disease, 5358 had a previous myocardial infarction. We estimated alcohol consumption by food-frequency questionnaire. FINDINGS: During a mean follow-up of 5 years, 920 men died. After adjustment for several potential confounders, moderate alcohol intake was associated with a significant decrease in total mortality (p=0.016). Compared with men who rarely or never drank alcohol, those who drank one to four drinks per month had a relative risk for total mortality of 0.85 (95% CI 0.69-1.05); for two to four drinks per week, the relative risk was 0.72 (0.58-0.89); for one drink per day 0.79 (0.64-9.96); and for two or more drinks per day 0.84 (0.55-1.26). INTERPRETATION: Men with previous myocardial infarction who consume small to moderate amounts of alcohol have a lower total mortality.