Bioavailability of Arsenic in Soil Impacted by Smelter Activities Following Oral Administration in Rabbits

This study determined the extent of arsenic (As) absorptionfrom soil from Anaconda, Montana. Prepubescent male and femaleSPF New Zealand White rabbits (5/sex/group) were given a singleoral (capsule) administration of soil (3900 ppm As) at threedifferent dose levels (0.2, 0.5, and 1.0 g of soil/kg, correspondingto 0.78, 1.95, and 3.9 mg As/kg, respectively). Standard groupsincluded untreated controls, an intravenous sodium arsenategroup (1.95 mg As/kg), and a gavage sodium arsenate group (1.95mg As/kg). Urine, cage rinse, and feces were collected at 24-hrintervals for 5 days and were analyzed for total As concentration.Clinical signs, body weights, and food consumption for treatedanimals were similar to controls. Maximum As concentrationswere obtained over the initial 24-hr collection interval. Adose-dependent delay in urinary As excretion, the major eliminationpathway, was observed in the oral soil group compared to thatin the gavage group. For the animals in the soil groups, approximately80% of the administered As dose was eliminated in the fecescompared to approximately 10 and 50% for the intravenous andoral gavage groups, respectively. The relative oral bioavailabilities(±SD) of As in the gavage and test soil groups basedon comparison with excreta data from the intravenous group wereapproximately 50±5.7 and 24±3.2%, respectively(after normalization of intravenous group's As recovery datato 100%). These results indicated that As in the soil was probablyin a less soluble and therefore a less absorbable form thansodium arsenate.     

Bioavailability of Phenytoin Following Oral Administration of Phenytoin-lipid Conjugates to Rats

The bioavailability of phenytoin was evaluated in rats upon oral administration of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxymethylphenytoin to 1,3-dimyristoylglyceride via a succinidyl linkage, to 2-(1,3-dimyristoyl-2-glyceryl)butyric acid and to 3-myristoyloxy-2-myristoyloxy-methylpropionic acid. Despite differences of the phenytoin plasma concentrations all three compounds approximately doubled the AUC compared with the dosing of phenytoin itself. The early onset and the long duration of the anticonvulsant activity after administration of the triglyceride-derived conjugate could be correlated to the increased phenytoin plasma levels. It is concluded that drug-lipid conjugates may be useful prodrugs for the oral delivery of poorly watersoluble drugs.     

Effect of Oral Probenecid Coadministration on the Chronic Toxicity and Pharmacokinetics of Intravenous Cidofovir in Cynomolgus Monkeys

In animals and humans, intravenous administration of the antiviralnucleotide analogue cidofovir results in a dose-limiting nephrotoxicitycharacterized by damage to the proximal tubular epithelial cells.Probenecid, a competitive inhibitor of organic anion transportin the proximal tubular epithelial cells, was evaluated forits effect on the chronic toxicity and pharmacokinetics of cidofovir.Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutiveweeks as a once weekly intravenous bolus injection at 0 (saline),0.1, 0.5, or 2.5 mg/kg/dose alone or at 2.5 mg/kg/dose in combinationwith probenecid (30 mg/kg/dose via oral gavage 1 h prior tocidofovir administration). Cidofovir-associated histopathologicalchanges were seen only in the kidneys, testes, and epididymides.Nephrotoxicity (mild to moderate cortical tubular epithelialcell karyomegaly, tubular dilatation, basement membrane thickening)was present only in monkeys receiving 2.5 mg/kg/dose cidofovirwithout probenecid. The incidence and severity of testicular(hypo- and aspermatogenesis) and epididymal (severe oligo- andaspenmia) changes were increased in monkeys administered cidofovirat 2.5 mg/kg/dose, either alone or in combination with oralprobenecid. Renal drug clearance was decreased between Weeks1 and 52 in the 2.5 mg/kg/dose groups and resulted in an increasedsystemic exposure to cidofovir (as measured by AUC) that wassignificantly greater in monkeys administered cidofovir alone(312% increase in males, 98% in females) than in those coadministeredprobenecid (32% increase in males, 3% in females). These resultsdemonstrate that oral probenecid coadministration protects againstthe morphological evidence of nephrotoxicity and the accompanyingdecrease in renal clearance in monkeys receiving chronic intravenouscidofovir treatment.     

Bioavailability of Enrofloxacin after Oral Administration to Fed and Fasted Pigs

Abstract: The disposition of enrofloxacin was measured after intravenous and oral administration to pigs. Eight clinically healthy pigs weighing 25 to 40 kg received a dose of 5 mg/kg intravenously and 10 mg/kg orally in both a fasted and a fed condition in a three-way cross-over design. Enrofloxacin was present in plasma for up to 72 hr after both intravenous and oral administration to fasted as well as fed pigs. The steady state volume of distribution was determined to 3.9±0.5 1/kg body weight which indicates that enrofloxacin was widely distributed in the body. The bioavailability was determined to 83±13% in fed and to 101±32% in fasted pigs. Based on the bioavailability and the resulting plasma concentrations it is concluded that a therapeutically active concentration for the most common porcine microbial pathogens are maintained for at least 24 hr after oral administration of 10 mg/kg body weight to fasted as well as to fed pigs. Ciprofloxacin which is an active metabolite of enrofloxacin was observed in plasma samples from all treated pigs, but the concentration never exceeded 0.1 μg/ml. During the first 24 hr after the administration of enrofloxacin the concentration of the metabolite made up less than 10% of the corresponding concentration of the parent compound.     

Bioavailability of Propranolol After Oral,Sublingual, and Intranasal Administration

The bioavailability of propranolol was compared after oral, sublingual, and intranasal administration in eight healthy male volunteers. Relative to the bioavailability after intranasal (in) administration, which was previously shown to be nearly complete (F _relin = 100%), the sublingual (sl) administration of a standard 10-mg tablet gave a bioavailability of F _relsl = 63 ± 22%, while the oral (or) administration yielded only F _relor = 25 ± 8%. The serum concentration–time curves of propranolol after sublingual administration resembled those of a sustained-release preparation. This sustained-release phenomenon after the sublingual route is reflected in the mean residence times (MRTs) of propranolol in the body (MRT_or = 5.7 ± 1.3 hr, MRT_sl - 6.4 ± 1.3 hr, MRT_in = 4.6 ± 1.0 hr; mean ± SD; N = 8). MRTs after sublingual administration were significantly longer than after the oral and the intranasal doses (P < 0.05 and P < 0.002, respectively).     

Enhanced Allergic Responses to House Dust Mite by Oral Exposure to Carbaryl in Rats

Epidemiological studies have demonstrated an association betweenuse of carbamate insecticides, including carbaryl, and increasedincidence of allergic asthma in farmers. In this study the effectof oral carbaryl exposure on the development of allergic responsesto house dust mite HDM) was examined in female Brown Norwayrats. Rats were gavaged for 2 weeks with 0, 2, 10, or 50 mg/kg/dayof carbaryl. They were sensitized with a subcutaneous injectionof HDM in aluminum hydroxide adjuvant 3 days after the beginningof carbaryl exposure and challenged with antigen via the trachea1 day after the final carbaryl ingestion. Two days after challenge,antigen-specific cell proliferation in pulmonary lymph nodeswas significantly higher in the 50 mg/kg group than in controls,while antigen-specific splenocyte proliferation was decreasedin groups dosed with 2, 10, and 50 mg/kg carbaryl. Total proteinand lymphocyte number in bronchoalveolar lavage (BAL) fluidwere also increased in the 50 mg/kg group. By 7 days after challenge,immune-mediated pulmonary inflammation (eosinophils), antigen-specificimmunoglobulin (Ig) E level in serum, and antigen-specific IgEand IgA levels in BAL fluid were significantly elevated in the50 mg/kg group. No apparent change was observed for lactatedehydrogenase and eminophil peroxidase in BAL fluid, while thenumber of BAL macrophages were decreased in groups dosed with10 and 50 mg/kg carbaryl. The results suggest that carbarylmay cause systemic immune suppression, while enhancing pulmonaryallergic responses to house dust mite antigen.     

大鼠口服雄黄后砷的药物动力学与毒代动力学研究

目的：探讨大鼠口服不同剂量雄黄后砷的药动学及毒代动力学规律。方法：氢化物发生．原子荧光光谱法测定大鼠单次灌胃3．5g·kg^-1和7．0g·kg^-1。雄黄后不同时间的血及组织中砷含量,拟合药动学模型,计算药动学参数。结果：大鼠单次口服雄黄后砷的药动学特征符合一室模型,3．5g·kg^-1和7．0g·kg^-1两个剂量组主要药动学和毒代动力学参数分别为：t1／2：15．87h和16．87h;Cmax：3．74×10^2μg·L^-1和6．89×10^2μg·L^-1;AUC0—6：9．86×10^3μg·h·L^-1和1．69×10^4μg·h·L^-1。砷在各组织均有分布,以肝、肾中含量最高。结论：大鼠口服不同剂量雄黄后砷在大鼠血中的药动学过程基本一致,在体内可造成蓄积。     

Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

Evaluation of the Teratogenicity and Pharmacokinetics of Diflunisal in Cynomolgus Monkeys

Evaluation of the Teratogenicity and Pharmacokinetics of Diflunisalin Cynomolgus Monkeys. ROWLAND, J. M., ROBERTSON, R. T., CUKIERSKI,M., PRAHALADA, S., TOCCO, D., and HENDRICKX, A. G. (1987). Fundam.Appl. Toxicol. 8, 51–58. This study examined the pharmacokineticsand potential teratogenicity of the nonsteroidal antiinflammatorydrug, diflunisal, in cynomolgus monkeys. Pregnant cynomolgusmonkeys were administered 0.5% methyl cellulose, 20 mg/kg/daydiflunisal, or 80 mg/kg/day diflunisal on Days 25 to 48 of gestation.There was no evidence of maternal toxicity, increased abortionrate, fetal growth retardation, or malformation. These datademonstrate that diflunisal is not teratogenic in cynomolgusmonkeys over a dosage range of 20 to 80 mg/kg/day. Peak plasmalevels of diflunisal were found 1 hr after oral administrationof [¹⁴C]diflunisal at a dosage of 60 mg/kg and declined to lowlevels by 24 hr. The plasma elimination half-life was calculatedto be 10.2 hr over the period of 1 to 8 hr postadministration.Intact diflunisal accounted for 96.4% of total plasma radioactivityat 0.5 hr and declined to a value of 74% at 8 hr. Plasma proteinbinding averaged greater than 99% over a concentration rangeof 62.5 to 250 µg/ml. Urinary excretion of diflunisaland metabolites averaged 66.5% of the dosage over the first4 days postadministration, compared with 0.8% in the feces.The majority of activity represented conjugates of diflunisal.Embryo concentrations of diflunisal on Days 35 to 37 of gestationwere 0.7 and 1.1% of maternal plasma level at 4 hr postadministrationof 20 or 60 mg/kg, respectively.     

Enhanced Bioavailability of Calcitonin Formulated with Alkylglycosides Following Nasal and Ocular Administration in Rats

Purpose. The purpose of this study was to characterize the effects of alkylglycosides on the bioavailability of calcitonin following nasal and ocular administration. Methods. A salmon calcitonin specific radioimmunoassay kit was used to measure calcitonin levels in anesthetized rats at various times after nasal or ocular administration of calcitonin formulated with saline or with octylmaltoside, a medium chain length alkylglycoside or tetradecylmaltoside, a long chain alkylglycoside. The extent of calcitonin absorption was determined directly from the plasma calcitonin level-time curve and the bioavailability of calcitonin was determined from the area under the plasma calcium level-time curve. The calcium level was determined using a colorimetric method. Results. When the nasal formulation contained calcitonin plus saline or 0.125% octylmaltoside, little or no calcitonin was absorbed. However, plasma calcitonin levels were increased and plasma calcium levels were decreased when the nasal formulation contained calcitonin plus 0.125% or 0.25% tetradecylmaltoside. Maximal calcitonin levels were observed 7.5-10 min after nasal administration of the formulation. Ocular administration of calcitonin formulated with tetradecylmaltoside also resulted in calcitonin absorption, but less calcitonin absorption was found after ocular administration than after nasal administration. Conclusion. The experimental data indicate that tetradecylmaltoside, but not octylmaltoside, can be effectively used to enhance the bioavailability of nasally and ocularly administered calcitonin.     

Stability of Liposomes in Vitro and Their Uptake by Rat Peyer's Patches Following Oral Administration

To evaluate the usefulness of liposomes as a carrier for the targeted delivery of antigens to gut-associated lymphoid tissue, liposomal stability and uptake by rat Peyer's patches were investigated. Liposomes composed of distearoylphosphatidylcholine, phosphatidylserine, and cholesterol (DSPC-liposome), or dipalmitoylphosphatidylcholine, phosphatidylserine, and cholesterol were stable in acidic solution (pH 2.0), diluted bile, and pancreatin solution. Following the oral administration of liposomes to rats, rhodamine B-PE incorporated in the lipid phase of DSPC-liposomes was preferentially taken up by Peyer's patches in the lower ileum. The uptake of rhodamine B-PE from DSPC-liposomes larger than 374 nm in mean diameter was high. Orally administered DSPC-liposomes of a large diameter thus appear to serve effectively as a vehicle for delivering antigens to Peyer's patches.     

Formulation Optimization and Bioavailability After Oral and Nasal Administration in Rabbits of Puerarin-Loaded Microemulsion

The main objective of the study was to investigate the efficacy of microemulsion (ME) to facilitate bioavailability of puerarin (PUE) after oral and nasal administration. The pseudo-ternary phase diagrams were constructed to screen the ME components and optimize the ME formulation. The optimized formulation for bioavailability assessment consisted of 20% Tween 80, 20% glycerin, and 1.6% ethyl oleate. The solubility (27.8 mg/mL) of PUE in ME was significantly improved compared to that (4.58 mg/mL) of crude PUE in water. The ME droplets were spherical with a mean particle diameter of 23.4 nm. After nasal (5 mg/kg) and oral (20 mg/kg) administration of a single dose of PUE as ME to fasted rabbits, the absolute bioavailability was 34.58% and 13.54%, respectively. It showed a shorter T_max (0.75 h) for nasal administration than that (1.0 h) for oral administration of PUE-loaded ME. The C_max of PUE-loaded ME was 0.55 μg/mL after nasal administration and 0.64 μg/mL after oral administration, respectively. The results showed that nasal administration might be a promising route to enhance the absorption of PUE in the form of ME.     

Pharmacokinetics of Uridine Following Ocular,Oral and Intravenous Administration in Rabbits

The pyrimidine nucleoside uridine has recently been reported to have a protective effect on cultured human corneal epithelial cells, in an animal model of dry eye and in patients. In this study, we investigate the pharmacokinetic profile of uridine in rabbits, following topical ocular (8 mg/eye), oral (450 mg/kg) and intravenous (100 mg/kg) administration. Blood and urine samples were serially taken, and uridine was measured by high-performance liquid chromatography-tandem mass spectrometry. No symptoms were noted in the animals after uridine treatment. Uridine was not detected in either plasma or urine after topical ocular administration, indicating no systemic exposure to uridine with this treatment route. Following a single intravenous dose, the plasma concentration of uridine showed a bi-exponential decay, with a rapid decline over 10 min, followed by a slow decay with a terminal half-life of 0.36 ± 0.05 h. Clearance and volume of distribution were 1.8 ± 0.6 L/h/kg and 0.58 ± 0.32 L/kg, respectively. The area under the plasma concentration-time curves (AUC) was 59.7 ± 18.2 μg·hr/ml, and urinary excretion up to 12 hr was ~7.7% of the dose. Plasma uridine reached a peak of 25.8 ± 4.1 μg/ml at 2.3 ± 0.8 hr after oral administration. The AUC was 79.0 ± 13.9 μg·hr/ml, representing ~29.4% of absolute bioavailability. About 1% of the oral dose was excreted in the urine. These results should prove useful in the design of future clinical and nonclinical studies conducted with uridine.     

Plasma Concentration Following Oral Administration of Di-and Flucloxacillin in Infants and Children

Abstract: The bioavailability of commercial liquid preparations of di- and flucloxacillin was compared in infants and children. The plasma concentrations following a dose of 12.5 mg/kg were equal within the two age groups. Infants 0-1 months old, however, demonstrated a better absorption than older children.     

Bioavailability of Phenytoin and Anticonvulsant Activity after Oral Administration of Phenytoin-bis-hydroxyisobutyrate to Rats

Pharmaceutical Research -     

Lung Tissue Responses and Sites of Particle Retention Differ between Rats and Cynomolgus Monkeys Exposed Chronically to Diesel Exhaust and Coal Dust

Several chronic inhalation bioassays of poorly soluble, nonfibrousparticles have resulted in an increased incidence of lung tumorsin rats, no increase in lung tumors in Syrian hamsters, andinconsistent results in mice. These results have raised concernsthat rats may be more prone than other species to develop persistentpulmonary epithelial hyperplasia, metaplasia, and tumors inresponse to the accumulation of inhaled particles. In addition,particle deposition and the rate of particle clearance fromthe lung differ between rats and primates, as does the anatomyof the centriacinar region. For these reasons, the usefulnessof pulmonary carcinogenicity data from rats exposed to highconcentrations of particles for quantitatively predicting lungcancer risk in humans exposed to much lower environmental oroccupational concentrations has been questioned. The purposeof this investigation was to directly compare the anatomicalpatterns of particle retention and the lung tissue responsesof rats and monkeys exposed chronically to high occupationalconcentrations of poorly soluble particles. Lung sections frommale cynomolgus monkeys and F344 rats exposed 7 hr/day, 5 days/weekfor 24 months to filtered ambient air, diesel exhaust (2 mgsoot/m³), coal dust (2 mg respirable particulate material/m³),or diesel exhaust and coal dust combined (1 mg soot and 1 mgrespirable coal dust/m³) were examined histopathologically.The relative volume density of particulate material and thevolume percentage of the total particulate material in definedpulmonary compartments were determined morphometrically to assessthe relative amount and the anatomic distribution of retainedparticulate material. In all groups, relatively more particulatematerial was retained in monkey than in rat lungs. After adjustmentfor differences between rat and monkey controls, the coal dust-and the combined diesel exhaust and coal dustexposed monkeysretained more particulate material than the coal dust- and thecombined diesel exhaust and coal dust-exposed rats, respectively.There was no significant difference in the relative amount ofretained particulate material between diesel exhaustexposedmonkeys and rats. Within each species, the sites of particleretention and lung tissue responses were the same for dieselsoot, coal dust, and the combined material. Rats retained agreater portion of the particulate material in lumens of alveolarducts and alveoli than monkeys. Conversely, monkeys retaineda greater portion of the particulate material in the interstitiumthan rats. Rats, but not monkeys, had significant alveolar epithelialhyperplastic, inflammatory, and septal fibrotic responses tothe retained particles. These results suggest that intrapulmonaryparticle retention patterns and tissue reactions in rats maynot be predictive of retention patterns and tissue responsesin primates exposed to poorly soluble particles at concentrationsrepresenting high occupational exposures.     

Cell Proliferation in Rat Forestomach Following Oral Administration of Styrene Oxide

A series of range-finding studies was conducted in a limitednumber of male F344 rats on the relation between cell proliferationand styrene oxide (SO) given as gavage doses in corn oil rangingfrom 550 to 1500 mg SO/kg. In each study, rats were injectedwith [³H](0.50 mCi/g, ip) at intervals from 1 to 48 hr afterdosing with SO. One hour later, stomachs were removed and fixedin formalin. Autoradiograins were prepared and labeling index(LI) was determined as the percentage of epithelial cells with³H-labeled nuclei. Mean LI increased with a peak at {small tilde}15 hr after one or nine doses of SO. The increases were multifocaland not restricted to the area near the limiting ridge. Themagnitude of the response in LI at 24 hr after dosing tendedto decrease with progressive multiple doses (3/week). Dose-relatedmorphologic lesions from SO (particularly submucosal) were multifocaland variable across the forestomach; they appeared unrelatedto LI in a given area. In a final study, groups of 10 rats weregiven a single dose of 0, 20, 50, 125, 250, 500, or 800 mg/kgand LI was determined 15 hr later. Mean LI was dose-relatedwith increases up to 250 mg/kg. A maximum response had apparentlybeen reached and higher doses did not cause any further increasein LI. The degree of involvement of cell proliferation in thetumorigenicity of SO remains uncertain; additional studies aresuggested to help in the understanding of such a possible relation.     

Oral Bioavailability of the Antiretroviral Agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from Three Formulations of the Prodrug Bis(pivaloyloxymethyl)-PMEA in Fasted Male Cynomolgus Monkeys

The bioavailability of PMEA from three oral formulations of the prodrug bis(POM)-PMEA has been evaluated in fasted male cynomolgus monkeys. The formulations examined included a hydroxy-propyl--cyclodextrin (HPBCD) complex, a PEG based cosolvent solution, and an aqueous suspension. Oral formulations containing ³H-bis(POM)-PMEA were compared to intravenous ³H-PMEA at 10.9 mg-eq/kg in a crossover study in four monkeys, with a 7 day washout period. No intact bis(POM)-PMEA or monoester were detected in plasma. Bioavailabilities of PMEA from the prodrug were 24.7 ± 6.5%, 27.3 ± 12.3% and 22.2 ± 15.6% for the HPBCD complex, PEG solution and aqueous suspension, respectively. The oral bioavailability of PMEA from bis(POM)-PMEA was not limited by dissolution rate of the prodrug. Data for the PEG cosolvent solution and suspension indicate that the prodrug could potentially be formulated as a soft gelatin capsule or a tablet.