Relative oral bioavailability of arsenic from contaminated soils measured in the cynomolgus monkey.

A number of studies have found that gastrointestinal absorption of arsenic from soil is limited, indicating that a relative oral bioavailability (RBA) adjustment is warranted when calculating risks from exposure to arsenic-contaminated soil. However, few studies of arsenic bioavailability from soil have been conducted in animal models with phylogenetic similarity to humans, such as nonhuman primates. We report here the results of a study in which the RBA of arsenic in soil from a variety of types of contaminated sites was measured in male cynomolgus monkeys. A single oral dose of each contaminated soil was administered to five adult male cynomolgus monkeys by gavage, and the extent of oral absorption was evaluated through measurement of arsenic recovery in urine and feces. Urinary recovery of arsenic following doses of contaminated soil was compared with urinary recovery following oral administration of sodium arsenate in water in order to determine the RBA of each soil. RBA of arsenic in 14 soil samples from 12 different sites ranged from 0.05 to 0.31 (5-31%), with most RBA values in the 0.1-0.2 (10-20%) range. The RBA values were found to be inversely related to the amount of arsenic present with iron sulfate. No other significant correlations were observed between RBA and arsenic mineralogic phases in the test soils. The lack of clear relationships between arsenic mineralogy and RBA measured in vivo suggests that gastrointestinal absorption of arsenic from soil may be more complex than originally thought, and subject to factors other than simple dissolution behavior.     

Bioavailability of Lead to Juvenile Swine Dosed with Soil from the Smuggler Mountain NPL Site of Aspen, Colorado

Bioavailability of lead (Pb) has become an issue in quantifyingexposure of sensitive populations and, where necessary, establishingcleanup levels for contaminated soil. Immature swine were usedas a model for young children to estimate the degree to whichPb from two fully characterized composite samples from the SmugglerMountain Superfund Site in Aspen, Colorado may be bioavailableto resident children. The composite soils contained 14,200 and3870 µg Pb/g of soil. Relative and absolute enteric bioavailabilitiesof Pb in soil (oral dose groups of 75,225, and 675 µgPb/kg body wt/day) were estimated by comparison with an orallyadministered soluble Pb salt (lead acetate = PbAc₂·3H₂O)(dose groups of 0, 75, and 225 µg Pb/kg body wt/day) andan intravenously administered aqueous solution of Pb (100 µgPb/kg/day) from the same trihydrate salt administered dailyfor 15 days to 50 juvenile swine. The biological responses (areaunder the blood Pb concentration-time curve, and the terminalliver-, kidney-, and bone-lead concentrations) produced by Pbfrom PbAc₂·3H₂O and lead-contaminated soils were determined.This study revealed Pb from soil containing 14,200 µgPb/g of soil had a bioavailability relative to Pb from PbAc(RBA), ranging from 56% based on the area under the blood leadconcentration-time curve (AUC) versus dose, to 86% based oncalculations from liver- Pb loading versus dose. Similarly,Pb from soil containing 3870 µg Pb/g of soil had an RBAranging from 58% based on the AUC versus dose, to 74% basedon calculations from liver- and kidney- Pb loading versus dose.Bioavailability of Pb in soils may be more or less than EPA'sdefault RBA of 60%, therefore, measuring site- specific RBAsprovides a basis for improved exposure and risk assessment.     

Cadmium toxicity for terrestrial invertebrates: taking soil parameters affecting bioavailability into account

Acute and chronic ecotoxicity tests with cadmium were conducted with the earthworm Eisenia fetida, the potworm Enchytraeus albidus and the springtail Folsomia candida. To assess the influence of the soil type on cadmium bioavailability, these tests were carried out in a standard artificial soil, in a sandy and a loamy field soil. It was not possible to evaluate the influence of soil parameters on the bioavailability on the basis of the experiments that were conducted in only three different soil types, therefore, literature data were also included. However, even in the same standard artificial soils, toxicity data in the literature for Eisenia fetida and Folsomia candida varied considerably. Consequently, no models could be developed that allow a normalization of the ecotoxicity of cadmium to parameters controlling bioavailability. In contrast to zinc, effect concentrations of cadmium for terrestrial invertebrates were always much higher than background concentrations. As the effect of aging on the bioavailability of cadmium was never taken into account, because toxicity experiments were always carried out in freshly spiked soils, these effect concentrations may even be regarded as conservative. Furthermore, the zinc–cadmium ratio in soils is usually so high that the risk of zinc ecotoxicity for terrestrial invertebrates will usually be much greater in comparison to cadmium ecotoxicity.     

Ecotoxicological study of arsenic and lead contaminated soils in former orchards at the Hanford site,USA

The purpose of this study was to assess ecotoxicity of former orchard soils contaminated with lead arsenate pesticides at the Hanford Site in Washington state (USA). Surface soil, plant, and invertebrate samples were collected from 11 sites in former orchard areas. Mean (standard deviation [SD]) for As and Pb in soil were 39.5 (40.6) and 208 (142) mg/kg dry wt, respectively (n = 11). These concentrations exceeded Hanford background levels but were similar to orchard soils elsewhere. In our study, As and Pb soil concentrations were positively and significantly correlated (r = 0.87, Bonferroni P < 0.05). Speciation of total inorganic As in soil (n = 6) demonstrated that As+5 was the dominant form (>99%). Mean (SD) for As and Pb in cheatgrass were 3.9 (7.9) and 12.4 (20.0) mg/kg dry wt, respectively (n = 11), while mean (SD) for As and Pb in darkling beetles were 5.4 (2.6) and 3.9 (3.0) mg/kg dry wt, respectively (n = 8). Linear regressions were constructed to estimate soil to cheatgrass and soil to darkling beetle uptake for As and Pb. These were significant (Bonferroni P < 0.05) only for cheatgrass versus soil (As) and darkling beetle versus soil (Pb). Standardized lettuce seedling and earthworm bioassays were performed with a subset of soil samples (n = 6). No significant effects (P > 0.05) were observed in lettuce survival or growth nor in earthworm survival or sublethal effects. Based on these bioassays, unbounded no observed effect concentrations (NOECs) in soil for As and Pb were 128 and 390 mg/kg dry wt, respectively. However, our range of soil concentrations generally overlapped a set of ecotoxicological benchmarks reported in the literature. Given uncertainty and limited sampling related to our NOECs, as well as uncertainty in generic benchmarks from the literature, further study is needed to refine characterization of As and Pb ecotoxicity in former orchard soils at the Hanford Site. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 10–20, 2014.     

Development of a priority list of chemical mixtures occurring at 1188 hazardous waste sites, using the hazdat database

Under the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund) section 104 mandate, as amended by the Superfund Amendments and Reauthorization Act (SARA) of 1986 USC 9604 (i)(2), the Agency for Toxic Substances and Disease Registry (ATSDR) is to identify individual substances and combinations of substances that pose the greatest public health hazard at hazardous waste sites. This has led to certain mandated activities of the Agency, including development of toxicological profiles, identification of data gaps, and, ultimately, establishment of a research agenda. The Agency has also developed HazDat, a database that captures pertinent information from public health assessments conducted at hazardous waste sites. As a preliminary step, data from sites have been analysed to identify the combinations of chemicals found in various environmental media. The most frequently found combinations were perchloroethylene (PERC) and trichloroethylene (TCE) in water (23.5% of sites); chromium (Cr) and lead (Ph) in soil (20.5%); benzene and toluene in air (3.5%); PERC, 1,1,1-trichloroethane (1,1,1-TCA) and TCE in water (11.6%); Cr, cadmium (Cd) and Pb in soil (12.0%); and benzene, PERC and TCE in air (2.2%). The findings of this analysis can be enhanced by factoring into the algorithm paramenters such as toxicity, source contribution, and likelihood of human exposure similar to that used for the Agency's priority list of 275 single substances. Assessment of the impact of chemical mixtures on human health is a formidable task, and estimating the toxicity of such mixtures, including the role of chemical interactions, is an equally demanding challenge. Because limited experimental data exist for chemical interactions, alternative methods such as predictive approaches and in vitro techniques are needed to address the many substances and their potential combinations.     

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.     

DISCONTINUOUS ORAL ABSORPTION PHARMACOKINETIC MODEL AND BIOAVAILABILITY OF 1-(2-FLUORO-5-METHYL-β-L-ARABINOFURANOSYL)URACIL (L-FMAU) IN RATS

1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)uracil (L-FMAU), the L isomer of FMAU, has shown potent activity against hepatitis B virus and Epstein--Barr virus. L-FMAU showed double peaks in the plasma concentration versus time profiles following oral administration to rats, indicating discontinuous oral absorption. The objective of this study was to characterize the bioavailability and pattern of L-FMAU absorption using a pharmacokinetic model which incorporated two separate absorption processes following oral administration of the nucleoside in an animal model, the rat. Simultaneous fitting of differential equations to L-FMAU plasma concentrations following oral and intravenous administration was performed using PCNONLIN. Total clearance of L-FMAU was moderate, averaging 0·47±0·16 L h⁻¹ (mean±SD). Distributional clearance averaged 0·18±0·14 L h⁻¹. The volume of the central compartment averaged 0·30±0·09 L, and the volume of the peripheral compartment averaged 0·15±0·08 L. The first-order absorption rate constants describing the first and second absorption phases averaged 1·22±1·56 and 4·14±5·42 h⁻¹, respectively. Oral bioavailability was calculated by three methods: AUC, urinary excretion data, and a discontinuous oral absorption pharmacokinetic model. Bioavailability averaged 0·59±0·16, 0·64±0·23, and 0·63±0·13, respectively, for the three methods. The discontinuous oral absorption pharmacokinetic model is a promising new method for estimating absorption from two phases and for calculating oral bioavailability.     

N-trimethyl chitosan (TMC)-modified microemulsions for improved oral bioavailability of puerarin: preparation and evaluation

Abstract

The aim of this research was to increase the oral bioavailability of puerarin by N-trimethyl chitosan-modified microemulsions (TMC-MEs) loaded with puerarin. Different concentrations of TMC-modified microemulsions were prepared in our study, and then evaluated for particle size, zeta potential, morphological observation and changes of the microenvironment polarity of inner oil core. It was shown that the zeta potential of the microemulsion was increased with the increasing concentration of TMC, and the peak value was achieved when the concentration of TMC was 3.0?mg/mL. The enhancement of the ratio of I₁/I₃ (the ratio between the first band and the third band of the emission fluorescence spectrum of pyrene, I₁?=?373?nm, I₃?=?384?nm) indicated that polarity of the inner core of TMC-MEs was increased with the addition of the modifier. Pharmacokinetic studies demonstrated that after oral administration of puerarin N-trimethyl chitosan (TMC)-modified microemulsions (PUE-TMEs) and puerarin microemulsions (PUE-MEs) to rats at a dose of 100?mg/kg, relative bioavailability was enhanced about 6.8- and 1.2-fold, respectively, compared to puerarin suspension (PUE-SUS) as control. It indicated that the TMC-MEs could be used as an effective formulation for enhancing the oral bioavailability of puerarin.     

Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects

Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38–40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111–120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.     

Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods

Introduction: The oral bioavailability of many lipophilic bioactives, such as pharmaceuticals and nutraceuticals, is relatively low due to their poor solubility, permeability and/or chemical stability within the human gastrointestinal tract (GIT). The oral bioavailability of lipophilic bioactives can be improved by designing food matrices that control their release, solubilization, transport and absorption within the GIT.

Areas covered: This article discusses the challenges associated with delivering lipophilic bioactive components, the impact of food composition and structure on oral bioavailability and the design of functional and medical foods for improving the oral bioavailability of lipophilic bioactives.

Expert opinion: Food-based delivery systems can be used to improve the oral bioavailability of lipophilic bioactives. There are a number of potential advantages to delivering lipophilic bioactives using functional or medical foods: greater compliance than conventional delivery forms; increased bioavailability and efficacy; and reduced variability in biological effects. However, food matrices are structurally complex multicomponent materials and research is still needed to identify optimum structures and compositions for particular bioactives.     

Bioavailability of Soil-Bound TCDD: Oral Bioavailability in the Rat

Bioavailability of Soil-Bound TCDD: Oral Bioavailability inthe Rat. SHU, H., PAUSTENBACH, D., MURRAY, F. J., MARPLE, L.,BRUNCK, B., DEI ROSSI, D., TEITELBAUM, P. (1988). Fundam ApplToxicol. 10, 648–654. The implications to the public healthof trace amounts of 2,3,7,8-TCDD in the environment are underevaluation by regulatory agencies in the United States and WesternEurope. One major consideration in such evaluations is the contributionto human exposure via ingestion of TCDD-contaminated soil. An80% figure is under consideration by some regulators for estimatedhuman exposure. A contractor for one agency has, in fact, useda value of 1007% bioavailability for estimating human bioavailability.Several studies have investigated the oral bioavailability ofTCDD from contaminated soil in animals. Most have reported estimatesof 25–50%, although one has reported <0.5 and 85%,depending on the source of the contaminated soil. This paperreports an oral bioavailability of approximately 43% in therat dosed with three environmentally contaminated soil samplesfrom Times Beach, Missouri. This figure did not change significantlyover a 500-fold dose range of 2 to 1450 ng TCDD/kg of body weightfor soil contaminated with approximately 2, 30, or 600 ppb ofTCDD. The relevance of animal oral bioavailability data forthe human remains to be evaluated. However, since regulatoryagencies use animal data for extrapolating to humans, the 43%or 25–50% figure would be more accurate than the 80 or100% estimates.     

溶出度试验预测固体制剂餐后生物利用度的研究进展

目的 综述近年来国内外溶出度试验方法的研究进展,为餐后生物利用度的预测提供理论依据。方法 综述药物的食物效应、溶出介质、溶出方法等对溶出度试验体内外相关性的影响。结果 药物性质、食物效应、溶出介质、溶出装置均影响溶出度方法的体内外相关性,均影响口服药物的餐后生物利用度。结论 在一致性评价任务重,国内餐后生物利用度研究经验少的前提下,开发能够预测餐后体内药动学的体外溶出方法,可以一定程度上减少研发风险和成本。     

Assessment of the toxicity of weathered petroleum hydrocarbon impacted soils to native plants from a site in the Canadian Subarctic

Remedial guidelines for petroleum hydrocarbons (PHCs) in soil aid in the mitigation of risks to human health and the environmental. However, some remediation guidelines may overestimate the potential for adverse effects to native plant species, contributing to unnecessary remedial efforts in attempts to meet the guidelines. At sites where PHC-contaminated soils undergo weathering, some PHCs may persist but with decreased bioavailability to organisms. In this study, the toxicity of both coarse and fine-grained subarctic soils, contaminated with weathered PHCs were assessed using five native plant species (Picea mariana, Achillea millefolium, Alnus viridis, Elymus trachycaulus and Salix bebbiana). Soil toxicity tests were conducted in a growth chamber with parameters set to simulate the site’s subarctic climate conditions. Reference toxicant tests using boric acid were conducted to provide confidence in the interpretation of the results for the PHC-contaminated soils, and also provide new information on the sensitivities of the four boreal species to boric acid. All plants exhibited reduced growth and germination rates as boric acid concentrations increased. Despite exceeding the Canada-wide standard guidelines for Fraction 3 PHCs, field-collected contaminated soils had no significant negative impacts on the growth (i.e., length, dry weight and emergence) of any of the plant species tested.

     

Systemic availability of arsenic from oral arsenic-trioxide used to treat patients with hematological malignancies

AIMS: Arsenic trioxide (As2O3) is increasingly used to treat hematological malignancies. This involves daily intravenous (i.v.) administration for 4-8 weeks, with its attendant drawbacks: inconvenience, risks and expense of maintaining suitable vascular access and hospitalization. We therefore developed an oral formulation, administered it to patients and set out to assess the resulting systemic bioavailability of arsenic. METHODS: With ethics committee approval, nine patients with refractory/relapsed acute myeloid leukemia were recruited after giving informed consent. On day 1, each received 10 mg As2O3 by i.v. infusion over 1 h. Each patient swallowed 10 mg As2O3 in 10 ml oral solution 24 h later (day 2) and on subsequent days thereafter. Prior to and until 48 h post-i.v. dosing, timed venous blood samples were drawn and corresponding plasma and whole blood arsenic concentrations were determined by atomic absorption spectroscopy. Systemic bioavailability was inferred from the area under the arsenic level versus time curve (AUC) using the trapezoidal rule. Day-1 AUC after i.v. dosing was taken to be 100% and that attributed to oral dosing (day 2) was then calculated. The 48-h arsenic levels in blood cells were calculated using hematocrit values and corresponding plasma and whole blood arsenic concentrations. RESULTS: Respective day-2 mean plasma and blood AUCs attributed to oral dosing were 99% and 87% of corresponding day-1 values. On average, 48-h blood cell arsenic levels were 270% greater than in plasma ( P=0.013). No patient suffered unexpected complications, and five went into remission. CONCLUSIONS: Compared with i.v. dosing, our oral As2O3 formulation was more convenient and cost effective, and the ensuing systemic bioavailability of arsenic appeared similar. Arsenic seemed to be concentrated in the cellular fraction of blood 48 h after starting As2O3 treatment.     

New method for bioavailability assessment of slow-release preparations of theophylline

Variability in an individual's clearance of theophylline is an important consideration when estimating bioavailability. A method is described for compensating for this problem, using the serum concentration of theophylline and urinary excretion data on its major metabolites to make an estimation of the clearance after oral administration using the intravenous dose as reference. The method is particularly useful for assessing the bioavailability of slow-release theophylline preparations.     

In vitro physiologically based extraction test (PBET) and bioaccessibility of arsenic and lead from various mine waste materials

In vivo models show that the bioavailability of soil contaminants varies between site and type of matrix. Studies demonstrated that assuming 100% bioavailability of arsenic (As) and lead (Pb) from soils and mine waste materials overestimates the risk associated with human exposure. In in vitro systems, the simulated bioavailability of a contaminant is referred to as the "bioaccessibility" and is used as an alternative quantitative indicator for in vivo derived bioavailability estimates. The general concept of the in vitro extraction test is to predict the bioavailability of inorganic substances from solid matrices by simulating the gastrointestinal tract (GIT) environment. The aims of this study were to: (1) investigate the bioaccessibility of As and Pb from various mine wastes, including tailings, heap leach, and waste rock, using a physiologically based extraction test (PBET); (2) validate the bioaccessibility values from PBET with in vivo bioavailability values measured using animal models; and (3) correlate PBET results with the bioavailability values measured from alternative in vivo models (rats and cattle, from Bruce, 2004). Significant correlation was observed between bioaccessibility values from PBET, and bioavailability values generated for both rats and cattle, demonstrating the potential to utilize PBET as a relatively inexpensive alternative to in vivo models for bioavailability assessment.     

Nanoparticle formulation of 11-keto-β-boswellic acid (KBA): anti-inflammatory activity and in vivo pharmacokinetics

Context: The oleo-gum-resin of Boswellia serrata Roxb. (Burseraceae) is widely used for the treatment of inflammatory diseases such as osteoarthritis, rheumatoid arthritis and cancer. Anti-inflammatory activity of 11-keto-β-boswellic acid (KBA) is impeded by poor oral bioavailability due to its high lipid solubility, rapid phase-1 metabolism and poor intestinal permeability.

Objective: This study developed a poly-dl-lactide-co-glycolide-based nanoparticle formulation of KBA to improve its oral bioavailability and in vivo anti-inflammatory activity.

Materials and methods: KBA was isolated from the oleo-gum resin of B. serrata, and its nanoparticle formulation (KBA-NPs) was prepared by the emulsion–diffusion–evaporation method. Oral bioavailability of KBA and KBA-NPs was studied at 50?mg/kg p.o. dose in Sprague–Dawley rats, and further evaluated for in vivo anti-inflammatory activity in carrageenan-induced rat paw oedema assay at the same dose level.

Results: The prepared KBA-NPs had a particle size of 152.6?nm with polydispersity index of 0.194, 79.7% entrapment efficiency and a cumulative 61.5% release of KBA from KBA-NPs, at 72?h. KBA-NPs showed 60.8% inhibition of rat paw oedema at 5?h as compared to 34.9% as that of KBA. The results of oral bioavailability study and in vivo anti-inflammatory activity showed 7- and 1.7-fold increase in bioavailability and anti-inflammatory activity, respectively, of KBA in KBA-NPs as compared to KBA alone.

Conclusion: The results of improved oral bioavailability and in vivo anti-inflammatory activity of KBA-NPs suggested successful development of KBA nanoparticle formulation.     

Determination of cepharanthine in rat plasma by LC–MS/MS and its application to a pharmacokinetic study

Context: Cepharanthine (CPA) has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the pharmacokinetic characteristics after oral or intravenous administration of CPA by using a sensitive and rapid LC–MS/MS method.

Materials and methods: A sensitive and rapid LC–MS/MS method was developed for the determination of CPA in Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (1?mg/kg) and the oral group (10?mg/kg). Blood samples (250?μL) were collected at designated time points and determined using this method. The pharmacokinetic parameters were calculated.

Results: The calibration curve was linear within the range of 0.1–200?ng/mL (r?=?0.999) with the lower limit of quantification at 0.1?ng/mL. After 1?mg/kg intravenous injection, the concentration of CPA reached a maximum of 153.17?±?16.18?ng/mL and the t_1/2 was 6.76?±?1.21?h. After oral administration of 10?mg/kg of CPA, CPA was not readily absorbed and reached C_max 46.89?±?5.25?ng/mL at approximately 2.67?h. The t_1/2 was 11.02?±?1.32?h. The absolute bioavailability of CPA by oral route was 5.65?±?0.35%, and the bioavailability was poor.

Discussion and conclusions: The results indicate that the bioavailability of CPA was poor in rats, and further research should be conducted to investigate the reason for its poor bioavailability and address this problem.     

Buccal Absorption of Testosterone and Its Esters Using a Bioadhesive Tablet in Dogs

Purpose. As the oral bioavailability of testosterone is very low because of its high first pass effect, buccal administration might present a viable alternative. In this study a buccal bioadhesive tablet was used in order to sustain the delivery and bypass the liver. Methods. Testosterone and testosterone acetate, propionate, enanthate and decanoate were investigated. The influence of the concentration of testosterone (10–50%) and testosterone esters (30%) on in vitro bioadhesion was investigated. The absolute (IV) and relative (oral) bioavailability of 60 mg testosterone or an equivalent amount of testosterone ester was determined in castrated male dogs. Results. Both the in vitro detachment force and the work of adhesion decreased gradually with an increasing amount of testosterone and for an increasing chain length of the esters, except in the case of testosterone enanthate. The in vivo results revealed that the bioavailability of testosterone was significantly higher (p < 0.05) than that of the esters, which is probably due to the lower solubility of the esters. The mean absolute bioavailability of testosterone from the bioadhesive tablet was 14.1%, while the mean relative bioavailability was 1370%. The buccal administration of testosterone via the bioadhesive tablet allowed the maintenance of the plasma level at above 3 ng/ml for 15 to 24 h. Conclusions. Buccal absorption of testosterone was significantly higher than that of its esters.