Measurement of arsenic bioavailability in soil using a primate model.

Several studies have shown limited absorption of arsenic from soils. This has led to increased interest in including measurements of arsenic relative bioavailability from soils in the calculation of risks to human health posed by arsenic-contaminated sites. Most of the information in the literature regarding arsenic bioavailability from soils comes from studies of mining and smelter sites in the western United States. It is unclear whether these observations are relevant to other types of arsenic-contaminated sites. In order to obtain information regarding arsenic bioavailability for other types of sites, relative bioavailability of arsenic from selected soil samples was measured in a primate model. Sodium arsenate was administered to five male Cebus apella monkeys by the intravenous and oral routes, and blood, urine, and feces were collected. Pharmacokinetic behavior of arsenic after intravenous administration and the fractions of dose excreted in urine and feces after both intravenous and oral doses were consistent with previous observations in humans. Soil samples from five waste sites in Florida (one from an electrical substation, one from a wood preservative treatment site, two from pesticide sites, and one from a cattle-dip vat site) were dried and sieved. Soil doses were prepared from these samples and administered orally to the monkeys. Relative bioavailability was assessed based on urinary excretion of arsenic following the soil dose compared with excretion following an oral dose of arsenic in solution. Differences in bioavailability were observed for different sites, with relative bioavailability ranging from 10.7 +/- 4.9% (mean +/- standard deviation) to 24.7 +/- 3.2% for the five soil samples. These observations, coupled with data in the literature, suggest limited oral bioavailability of arsenic in soils from a variety of types of arsenic-contaminated sites.     

Characterization of gastrointestinal drug absorption in cynomolgus monkeys

Possible factors of species differences in gastrointestinal drug absorption between cynomolgus monkeys and humans were examined using several commercial drugs. Oral bioavailability (BA) of acetaminophen, furosemide, and propranolol in cynomolgus monkeys was significantly lower than that in humans. From the pharmacokinetic analysis, these drugs were found to show the low fraction absorbed into portal vein (FaFg), suggesting that the low BA in cynomolgus monkeys was attributed mainly to the gastrointestinal absorption processes. The gastric emptying rate (GER) calculated from plasma concentration profiles after oral administration of acetaminophen in cynomolgus monkeys was similar in humans. The gastrointestinal transit time (GITT) in cynomolgus monkeys was only slightly shorter than that in humans. On the other hand, it was demonstrated that the apparent intestinal permeability (Papp) of five drugs to cynomolgus monkey intestine was lower than that to rat intestine; especially propranolol and furosemide showed the remarkably low Papp. The expression levels of mRNAs of efflux transporters analyzed by real-time RT-PCR indicated that mRNA expression levels of MDR1, MRP2, and BCRP in monkey intestine were significantly higher than those in human intestine. This result suggested that low oral absorption of furosemide in cynomolgus monkeys was attributed to the high activities of efflux transporters in its intestinal membrane. Results of in vivo PK analysis clearly showed that FaFg values of propranolol and acetaminophen in cynomolgus monkeys were markedly lower than those in humans. Since propranolol and acetaminophen were the drug with high membrane permeability, it was considered that the high first-pass metabolism in the enterocytes was a main factor of their low FaFg in cynomolgus monkeys. In conclusion, it was demonstrated that the high activities of efflux transporters and/or metabolizing enzymes in the intestinal membrane are possible factors to cause poor oral absorption of drugs in cynomolgus monkeys.     

In vitro and in vivo evaluation of the metabolism and bioavailability of ester prodrugs of mgs0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid), a potent metabotropic glutamate receptor antagonist.

MGS0039 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid) has been identified as a potent and selective antagonist for metabotropic glutamate receptors. However, the oral bioavailability of MGS0039 is 10.9% in rats, due to low absorption. Several prodrugs, synthesized to improve absorption, exhibited 40 to 70% bioavailability in rats. This study investigated in vitro metabolism using liver S9 fractions from both cynomolgus monkeys and humans and oral bioavailability in cynomolgus monkeys to select the prodrug most likely to exhibit optimal pharmacokinetic profiles in humans. In monkeys, transformation to active substance was observed (5.9-72.8%) in liver S9 fractions, and n-butyl, n-pentyl, 3-methylbutyl, and 4-methylpentyl ester prodrugs exhibited high transformation ratios (>64%). Cmax levels and F values after oral dosing increased to 4.1- to 6.3-fold and 2.4- to 6.3-fold, respectively, and a close relationship between transformation ratios and Cmax and F values was observed, indicating that the hydrolysis rate in liver S9 fractions is the key factor in determining oral bioavailability in monkeys. In humans, n-hexyl, n-heptyl, n-octyl, 5-methylbutyl, and 6-methylpentyl ester prodrugs exhibited high transformation ratios (>65%) in liver S9 fractions. With these prodrugs, n-hexyl, n-heptyl, and 5-methylpentyl ester, almost complete recovery (96-99%) was obtained. Given the transformation ratio, we anticipated that the n-heptyl alkyl ester prodrug would exhibit the highest oral bioavailability of active substances in humans, if the hydrolysis rate in liver S9 fractions is indeed the key factor in determining oral bioavailability in humans. On this basis, MGS0210 (3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid n-heptyl ester) seems to be a promising candidate among MGS0039 prodrugs.     

In vivo and in vitro methods for evaluating soil arsenic bioavailability: relevant to human health risk assessment

Arsenic (As) is the most frequently occurring contaminant on the priority list of hazardous substances, which lists substances of greatest public health concern to people living at or near U.S. National Priorities List site. Accurate assessment of human health risks from exposure to As-contaminated soils depends on estimating its bioavailability, defined as the fraction of ingested As absorbed across the gastrointestinal barrier and available for systemic distribution and metabolism. Arsenic bioavailability varies among soils and is influenced by site-specific soil physical and chemical characteristics and internal biological factors. This review describes the state-of-the science that supports our understanding of oral bioavailability of soil As, the methods that are currently being explored for estimating soil As relative bioavailability (RBA), and future research areas that could improve our prediction of the oral RBA of soil As in humans. The following topics are addressed: (1) As soil geochemistry; (2) As toxicology; (3) in vivo models for estimating As RBA; (4) in vitro bioaccessibility methods; and (5) conclusions and research needs.     

Species Difference in Intestinal Absorption Mechanism of Etoposide and Digoxin between Cynomolgus Monkey and Rat

Purpose  The oral bioavailability of some therapeutic agents is markedly lower in cynomolgus monkeys than in humans. We investigated small-intestinal absorption of the P-glycoprotein (P-gp) substrates etoposide and digoxin in monkeys to clarify the influence of efflux transport on their intestinal permeability. Methods  The pharmacokinetics of etoposide and digoxin was examined in monkeys and rats after oral and intravenous administration. Intestinal permeability and segmental differences in permeability were investigated with an Ussing-type chamber. Results  The bioavailability of etoposide was 12.9 and 13.9% in monkeys and rats, respectively. Total body clearance of etoposide in monkeys was much less than hepatic blood flow, suggesting that the bioavailability would be limited at intestinal absorption. Marked vectorial transport of etoposide in the secretory direction was observed in rats, especially in the lower small intestine, and segmental differences were consistent with the distribution of P-gp expression. Vectorial transport was minimal in monkey small intestine. Our kinetic analysis indicated that P-gp contributes little to the intestinal permeability of etoposide and digoxin in monkeys, and apical uptake is rate-limiting. Conclusion  Low bioavailability of etoposide in monkeys is due to poor intestinal uptake resulting from low influx from the apical side, rather than secretion via P-gp.     

Species differences in intestinal metabolic activities of cytochrome P450 isoforms between cynomolgus monkeys and humans

The oral bioavailability of some drugs is markedly lower in cynomolgus monkeys than in humans. One of the reasons for the low bioavailability in cynomolgus monkeys may be the higher metabolic activity of intestinal CYP3A; however, the species differences in intestinal metabolic activities of other CYP isoforms between cynomolgus monkeys and humans are not well known. In the present study, we investigated the intrinsic clearance (CL(int)) values in pooled intestinal microsomes from cynomolgus monkeys and humans using 25 substrates of human CYP1A2, CYP2J2, CYP2C, and CYP2D6. As in humans, intestinal CL(int) values of human CYP1A2 and CYP2D6 substrates in cynomolgus monkeys were low. On the other hand, intestinal CL(int) values of human CYP2J2 and CYP2C substrates in cynomolgus monkeys were greatly higher than those in humans. Using immunoinhibitory antibodies and chemical inhibitors, we showed that the higher intestinal CL(int) values of the human CYP2J2 and CYP2C substrates in cynomolgus monkeys might be caused by monkey CYP4F and CYP2C subfamily members, respectively. In conclusion, there is a possibility that the greatly higher metabolic activity of CYP2C and CYP4F in cynomolgus monkey intestine is one of the causes of the species difference of intestinal first-pass metabolism between cynomolgus monkeys and humans.     

Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey.

Oral bioavailability of some drugs is substantially lower in cynomolgus monkeys than in various other species, including humans. In the present study, midazolam was used as a model drug to investigate the reason for the lower bioavailability in these monkeys. The bioavailability of midazolam after oral administration was minimal in monkeys and rats, being only 2.1 and 1.1%, respectively. In monkeys, this low bioavailability could not be explained simply in terms of a hepatic first-pass effect. To examine the roles of intestinal metabolism and transport, we evaluated apical-to-basal and basal-to-apical transport of midazolam, and the formation of metabolites in small intestinal tissues using an Ussing-type chamber. The values of mucosal extraction ratio were estimated to be 0.97, 0.93, and 0.89 during apical-to-basal transport in the upper, middle, and lower small intestine of monkeys, respectively, whereas the corresponding values for rats were close to zero, indicating that extensive metabolism of midazolam occurs, particularly in the upper region of the small intestine in monkeys, but not rats. Interestingly, formation of the metabolites was much greater during transport in the apical-to-basal direction than in the basal-to-apical direction, and this could be well explained by a mathematical model based on the assumption that extensive metabolism is associated with the uptake process of midazolam from the apical cell surface. Thus, we conclude that an asymmetric distribution of metabolic activity in the small intestine, leading to extensive metabolism during uptake from the apical cell surface, accounts for the minimal oral bioavailability of midazolam in cynomolgus monkeys.     

The species differences of intestinal drug absorption and first-pass metabolism between cynomolgus monkeys and humans

In order to elucidate the causes of the species differences in the oral bioavailability (BA) between cynomolgus monkeys and humans, the contributions of first-pass metabolism and intestinal absorption were investigated. Typical substrates of cytochrome P450 enzymes, UDP-glucuronosyltransferase enzymes and efflux transporters were selected, and the BA, the hepatic availability (Fh) and the fraction dose absorbed from gastro-intestinal tract (Fa*Fg) were calculated from pharmacokinetic analysis after oral and intravenous administration in cynomolgus monkeys. In addition, in vitro metabolism was investigated using liver and intestinal microsomes to evaluate the relationship between in vivo and in vitro results. The BA of cynomolgus monkeys was low compared with that in humans with most of the drugs tested, and not only Fh but also Fa*Fg contributed significantly to the low BA in cynomolgus monkeys. When Fh was evaluated in in vitro experiments, it correlated well with the in vivo Fh. However, although the metabolic activities of CYP3A4 substrates were high in cynomolgus monkey intestinal microsomes, those of the other substrates were low or not detected. These findings suggested that the species differences and low BA in cynomolgus monkeys could be mostly attributed not only to hepatic first-pass metabolism but also to the intestinal absorption process. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4343–4353, 2009     

Dermal absorption of arsenic from soils as measured in the rhesus monkey.

Regulatory agencies have relied on dermal absorption data for soluble forms of arsenic as the technical basis for specific absorption values that are used to calculate exposure to arsenic in weathered soil. These evaluations indicate that percutaneous absorption of arsenic from soil ranges from 3.2 to 4.5% of the dermally applied dose, based on studies of arsenic freshly mixed with soil. When this value is incorporated into risk assessments and combined with other assumptions about dermal exposures to soil, the conclusion is often that dermal exposure to arsenic from soil may contribute significantly to overall exposure to arsenic in soil. Prior characterization research has indicated that the solubility of arsenic in soil varies, depending on the provenance of the soil, the source of the arsenic, and the chemical interaction of arsenic with other minerals present within the soil matrix. Weathering produces forms of arsenic that are more tightly bound within the soil and less available for absorption. Our research expands on prior in vivo studies to provide insights into the potential for dermal absorption of arsenic from the more environmentally relevant substrate of soil. Specifically, two soils with very high concentrations of arsenic were evaluated under two levels of skin hydration. One soil, containing 1400 mg/kg arsenic, was collected adjacent to a pesticide production facility in New York. The other soil, containing 1230 mg/kg arsenic, was collected from a residential area with a history of application of arsenical pesticides. Although the results of this research are constrained by the small study size dictated by the selection of an animal research model using monkeys, the statistical power was optimized by using a "crossover" study design, wherein each animal could serve as its own comparison control. No other models (animal or in vitro) were deemed adequate for studying the dermal absorption of soil arsenic. Our results show dermal absorption of soluble arsenic in solution to be 4.8 +/- 5.5%, which is similar to results reported earlier for arsenic in solution (and used by regulatory agencies in recommendations regarding dermal absorption of arsenic). Conversely, absorption following application of arsenic in the soil matrices resulted in mean estimated arsenic absorption of 0.5% or less for all soils, and all individual estimates were less than 1%. More specifically, following application of arsenic-bearing soils to the abdomens of monkeys, urinary arsenic excretion could not be readily distinguished from background. This was true across all five soil-dosing trials, including application of the two dry soils and three trials with wet soil. These findings are consistent with our understanding of the environmental chemistry of arsenic, wherein arsenic can be present in soils in complexed mineral forms. This research addresses an important component involved in estimating the true contribution of percutaneous exposures to arsenic in soil relative to exposures via ingestion. Our findings suggest that dermal absorption of arsenic from soil is truly negligible, and that EPA's current default assumption of 3% dermal absorption of arsenic from soils results in significant overestimates of exposure.     

Bioavailability of chlorothiazide from 50, 100, and 250 mg solution doses

The bioavailability of chlorothiazide was examined following single oral solution doses to eight healthy male volunteers. Drug was administered in 250ml of water after overnight fast. Bioavailability was determined by measuring 72 h urinary recovery of unchanged drug. Mean urinary recovery from 50, 100, and 250 mg doses was, respectively, 28.3, 47.0, and 83.3 mg, representing 56.4, 47.0, and 33.3 per cent of the administered dose. The correlation coefficient between dose size and percentage recovery was ?0.662. These results add support to previous suggestions that the absorption of chlorothiazide from the gastrointestinal tract is saturable, and that the bioavailability of chlorothiazide may be similar to that of hydrochlorothiazide when these compounds are administered in the same dosage range.     

Marked species differences in the bioavailability of midazolam in cynomolgus monkeys and humans

The bioavailability (F) of midazolam in cynomolgus monkeys (0.02) was markedly lower than that in humans (0.24-0.46) and the reason for this difference in F between the two species was investigated. Based on the area under the plasma concentration-time curve after intravenous and intraportal infusion to cynomolgus monkeys, the hepatic availability (F(h)) was estimated as 0.66. The fraction of dose absorbed (F(a)) estimated from the single-pass intestinal perfusion method was 1.0 in cynomolgus monkeys. The intestinal availability (F(g) = F/F(a)/F(h)) was calculated as 0.03 in cynomolgus monkeys. Since the F(a) of midazolam has been reported to be almost 1.0 in humans, F(h) and F(g) were calculated as 0.33-0.76 and 0.46-1.00 when the reference values for hepatic blood flow (1026-1530 ml h(-1) kg(-1)) were used. In conclusion, the main reason for low F in cynomolgus monkeys was the markedly higher first-pass intestinal metabolism seen in cynomolgus monkeys compared with humans.     

Oral bioavailability of cyclotrimethylenetrinitramine (RDX) from contaminated site soils in rats

Cyclotrimethylenetrinitramine (RDX), a commonly used military explosive, was detected as a contaminant of soil and water at Army facilities and ranges. This study was conducted to determine the relative oral bioavailability of RDX in contaminated soil and to develop a method to derive bioavailability adjustments for risk assessments using rodents. Adult male Sprague-Dawley rats preimplanted with femoral artery catheters were dosed orally with gelatin capsules containing either pure RDX or an equivalent amount of RDX in contaminated soils from Louisiana Army Ammunition Plant (LAAP) (2300 microg/g of soil) or Fort Meade (FM) (670 microg/g of soil). After dosing rats, blood samples were collected from catheters at 2-h intervals (2, 4, 6, 8, 10, and 12) and at 24 and 48 h. RDX levels in the blood were determined by gas chromatography. The results show that the peak absorption of RDX in blood was 6 h for neat RDX (1.24 mg/kg) and for RDX from contaminated soil (1.24 mg/kg) of LAAP. Rats dosed with RDX-contaminated FM soil (0.2 mg/kg) showed peak levels of RDX in blood at 6 h, whereas their counterparts that received an identical dose (0.2 mg/kg) of neat RDX showed peak absorption at 4 h. The blood levels of absorbed RDX from LAAP soil were about 25% less than for neat RDX, whereas the bioavailability of RDX from FM soils was about 15% less than that seen in rats treated with neat RDX (0.2 mg/kg). The oral bioavailability in rats fed RDX in LAAP soil and the FM soil was reduced with the neat compound but decrease in bioavailability varied with the soil type.     

Vaccinium myrtillus anthocyanosides pharmacokinetics in rats

The pharmacokinetics of Vaccinium myrtillus anthocyanosides (VMA) have been investigated in male rats. After intravenous administration anthocyanosides undergo a rapid body distribution and their disappearance from the blood is suitably fitted by a three-compartment pharmacokinetic model. The elimination occurs mostly through urine and bile. After a single oral administration the plasma concentrations of anthocyanosides reach peak level after 15 min and then rapidly decline within 2 h. The extent of cumulative urinary and biliary elimination together with the gastrointestinal recovery demonstrates an absorption of about 5%. No hepatic first-pass effect has been observed. Despite of the modest gastrointestinal absorption and the low absolute bioavailability (1.2% of the administered dose), the plasmatic peak levels (2-3 micrograms/ml) measured after the oral treatment are in the range of biological activity reported for these substances.     

3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization

Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.     

The pharmacokinetics of a thiazole benzenesulfonamide beta 3-adrenergic receptor agonist and its analogs in rats, dogs, and monkeys: improving oral bioavailability.

The pharmacokinetics and oral bioavailability of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethylphenyl]thiazol-2-yl]benzenesulfonamide (1), a 3-pyridyl thiazole benzenesulfonamide beta3-adrenergic receptor agonist, were investigated in rats, dogs, and monkeys. Systemic clearance was higher in rats (approximately 30 ml/min/kg) than in dogs and monkeys (both approximately 10 ml/min/kg), and oral bioavailability was 17, 27, and 4%, respectively. Since systemic clearance was 25 to 40% of hepatic blood flow in these species, hepatic extraction was expected to be low, and it was likely that oral bioavailability was limited either by absorption or a large first-pass effect in the gut. The absorption and excretion of 3H-labeled 1 were investigated in rats, and only 28% of the administered radioactivity was orally absorbed. Subsequently, the hepatic extraction of 1 was evaluated in rats (30%) and monkeys (47%). The low oral bioavailability in rats could be explained completely by poor oral absorption and hepatic first-pass metabolism; in monkeys, oral absorption was either less than in rats or first-pass extraction in the gut was greater. In an attempt to increase oral exposure, the pharmacokinetics and oral bioavailability of two potential prodrugs of 1, an N-ethyl [(R)-N-[4-[2-[ethyl[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide; 2] and a morpholine derivative [(R)-N-[4-[2-[2-(3-pyridinyl)morpholin-4-yl]ethyl]phenyl]-4-[4-[4-(trifluoromethyl)- phenyl]thiazol-2-yl]benzenesulfonamide; 3], were evaluated in monkeys. Conversion to 1 was low (<3%) with both derivatives, and neither entity was an effective prodrug, but the oral bioavailability of 3 (56%) compared with 1 (4%) was significantly improved. The hypothesis that the increased oral bioavailability of 3 was due to a reduction in hydrogen bonding sites in the molecule led to the design of (R)-N-[4-[2-[[2-hydroxy-2-(pyridin-2-yl)ethyl]amino]ethyl]phenyl]-4-[4-(4-trifluoromethylphenyl)thiazol-2-yl]benzenesulfonamide (4), a 2-pyridyl beta3-adrenergic receptor agonist with improved oral bioavailability in rats and monkeys.     

Applications and Simulations of a Discontinuous Oral Absorption Pharmacokinetic Model

Purpose. To illustrate the application of a discontinuous oral absorption model to cimetidine and ranitidine plasma concentration versus time data to demonstrate the use of the model for drugs which display discontinuous oral absorption profiles, and to illustrate the effect of various model parameters on plasma drug concentration versus time profiles and bioavailability. Methods. A discontinuous oral absorption model was used to fit ranitidine and cimetidine serum concentrations following oral and intravenous administration. The model was also used to simulate bioavailability and plasma concentrations versus time profiles for various parameter values. Results. Serum concentrations following administration of ranitidine and cimetidine were well described by the model, and parameter estimates obtained were in agreement with literature values. Simulations demonstrate the effects of various absorption parameters and gastrointestinal tract transit parameters on bioavailability and plasma concentration profiles. Conclusions. This discontinuous oral absorption pharmacokinetic model can be a useful tool in characterizing absorption phases, disposition, and bioavailability of drugs exhibiting two absorption peaks following oral administration.     

Enteric-coating capsulation of insulinomimetic vanadyl sulfate enhances bioavailability of vanadyl species in rats

In recent years, there have been improvements in the treatment of type 2 diabetes by oral administration of vanadyl sulfate (VOSO4, VS). The maintenance of vanadyl levels in the blood of subjects with type 2 diabetes was found to be important for the insulinomimetic activity of VS. However, owing to low bioavailability of VS and the development of mild gastrointestinal symptoms and side-effects in some subjects, it is necessary to design more effective and safer dosages of VS. After discovering that VS is absorbed more thoroughly at the ileum than at other gastrointestinal sites, we investigated the absorption processes following oral administration of VS by preparing enteric-coated capsules (ECC). Although Cmax values were unchanged by the dosage forms, Tmax and MRT values associated with the enteric-coating capsulation were prolonged when compared with those observed with use of gelatin capsules (GC). An important finding was that the bioavailability of VS from ECC (9.8%) was almost double that of VS from either GC (4.0%) or the solution (4.8%). Administration of VS-containing ECC to diabetic patients is proposed to improve vanadyl absorption over that achieved by the administration of either GC or the solution.     

Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.     

Bioavailability of Arsenic in Soil and House Dust Impacted by Smelter Activities Following Oral Administration in Cynomolgus Monkeys

This study was conducted to determine the extent of arsenic(As) absorption from soil and house dust impacted by smelteractivities near Anaconda, Montana. Female cynomolgus monkeyswere given a single oral administration via gelatin capsulesof soil (0.62 mg As/kg body wt) or house dust (0.26 mg As/kgbody wt), or soluble sodium arsenate by the gavage or intravenousroute of administration (0.62 mg As/kg body wt) in a crossoverdesign with a minimum washout period of 14 days. Urine, feces,and cage rinse were collected at 24-hr intervals for 168 hr.Blood was collected at specified time points and area underthe curves (AUCs) was determined. Arsenic concentrations forthe first 120 hr, representing elimination of greater than 94%of the total administered dose for the three oral treatmentgroups, were <0.02 1 to 4.68 zg/ml for the urine and <0.24to 31.1 µg/g for the feces. In general, peak concentrationsof As in the urine and feces were obtained during the collectionintervals of 0–24 and 24–72 hr, respectively. Themain pathway for excretion of As for the intravenous and gavagegroups was in the urine, whereas for the soil and dust groups,it was in the feces. Mean absolute percentage bioavailabilityvalues based on urinary excretion data were 68, 19, and 14%for the gavage, house dust, and soil treatments, respectively,after normal ization of the intravenous As recovery data to100%. Correspond ing absolute bioavailability values based onblood were 91, 10, and 11%. The bioavailabiity of soil and housedust As relative to soluble As (by gavage) was between 10 and30%, depending upon whether urinary or blood values were used.These findings suggest that risks associated with the ingestionof As in soil or dust will be reduced compared to ingestionof comparable quantities of As in drinking water.     

A pharmacokinetic study to evaluate the absolute bioavailability of triamcinolone acetonide following inhalation administration.

Triamcinolone acetonide is a glucocorticoid administered by oral inhalation in the management of asthma. With oral inhalation of glucocorticoids, systemic absorption can come from oropharyngeal, gastrointestinal, or airway deposition of the drug. The objectives of this study were to determine the absolute bioavailability of triamcinolone acetonide following inhalation administration and to delineate the airway contribution of triamcinolone acetonide absorption relative to the absolute bioavailability. All subjects received a 5-minute 400 mcg intravenous infusion of triamcinolone acetonide and a single 800 mcg dose of inhaled triamcinolone acetonide with and without oral charcoal administration in a randomized three-way crossover fashion. The oral charcoal allowed for isolating the pulmonary component of absorption by adsorbing the oropharyngeal and gastrointestinal deposited drug. The mean (+/- SD) absolute bioavailability value for inhaled triamcinolone acetonide was 25% (8.75%). Delineation of the airway contribution of triamcinolone acetonide absorption showed that 10.4% of an inhaled dose is absorbed as triamcinolone acetonide from the lungs. Mean (+/- SD) total body clearance was rapid at 0.57 (0.12) L/hr/kg. The mean (+/- SD) apparent volume of distribution following the intravenous dose was a low 1.96 (0.31) L/kg. No significant differences were noted in the apparent terminal elimination half-life of triamcinolone acetonide (approximately 2.4 hr) between treatments.