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

Bioavailability of Soil-Bound TCDD: Dermal Bioavailability inthe Rat. SHU, H., TEITELBAUM, T., WEBB, A. S., MARPLE, L., BRUNCK,B. DEI ROSSI, D., MURRAY, J., AND PAUSTENBACH, D. (1988). Fundam.Appl. Toxicol. 10, 335-343. 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD), an unwanted by-product formed during the manufactureof hexachlorophene and phenoxyherbicides, has been found asan environmental contaminant in many U.S. and Western Europeansites. This study examines in the rat the degree of dermal absorptionof TCDD bound to soil. Such information would assist regulatoryagencies in evaluating the degree of exposure of humans whocome in contact with TCDD-contaminated soil. Several parameterswhich may influence dermal absorption were studied, includingTCDD dose, duration of contact, presence of crankcase oil asa co-contaminant, and environmentally contaminated vs laboratory-preparedsoil. The dermal penetration of TCDD following 4 hr of contactwith skin was approximately 60% of that following 24 hr of contact(P 0.05). Following 24 hr of contact with the skin, the degreeof dermal uptake of TCDD contaminated soil was approximately1% of the administered dose. Under the conditions of the presentstudy, the degree of uptake does not appear to be influencedto any significant extent by the concentration of TCDD on soil,the presence of crankcase oil as co-contaminants, or by environmentallyvs laboratory-contaminated soil. Although a number of parametersexamined in this study did not significantly influence the degreeof dermal absorption of TCDD in the rat following 24 hr of contactwith the contaminated soil, the unqualified use of the 1% valueto estimate human exposure would overestimate human exposure,since there is general agreement among researchers that ratskin tends to be more permeable than human skin to highly lipid-solublecompounds such as TCDD.     

口服胸腺肽微球在大鼠体内的药代动力学和生物利用度

目的 :研究胸腺肽微球在大鼠体内的药动学和生物利用度。方法 :用高效液相色谱测定大鼠血中胸腺肽浓度 ,3P87程序计算参数。结果 :胸腺肽微球的药动学参数分别为 :Cmax=2 8.6 0± 9.43μg/ml,tmax=2 10min ,t1/ 2 (β) =144 .40± 19.78min ,AUC0～∞ =76 6 2 .0 3± 70 4.36 μg·min/ml,相对于胶囊剂内容物的生物利用度是 2 38.8%。结论 :大鼠对胸腺肽微球的吸收明显优于胶囊剂内容物。     

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

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Risperidone: Effects of Formulations on Oral Bioavailability

The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (C_max, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80–120% (80–125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.     

Why is it Challenging to Predict Intestinal Drug Absorption and Oral Bioavailability in Human Using Rat Model

Purpose To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat.Materials and Methods The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.Results No correlation (r ² = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r ² = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r ² > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.Conclusions The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.     

救必应酸在大鼠体内的口服生物利用度研究

摘 要 目的：研究救必应酸在大鼠体内药动学和口服生物利用度。方法: 建立测定大鼠血浆中救必应酸浓度的RP HPLC法。考察大鼠经灌胃和尾静脉给予40 mg·kg^-1的救必应酸后血药浓度变化。采用3p97软件计算分析药动学参数和口服生物利用度。结果: 灌胃组大鼠的C_max为（0.81±0.22）μg·mL^-1,T_max为（45.24±5.13） min,T_1/2为（101.47±8.25） min,AUC为（76.3±13.68）μg·min^-1·mL^-1;静脉注射组的T_1/2为（73.68±11.02） min,AUC为（1 687.4±29.54）μg·min^-1·mL^-1。救必应酸口服利用度为4.52%。结论:救必应酸的口服生物利用度较差。     

Rat embryonic palatal shelves respond to TCDD in organ culture

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), a highly toxic environmental contaminant, is teratogenic in mice, inducing cleft palate (CP) and hydronephrosis at doses which are not overtly maternally or embryo toxic. Palatal shelves of embryonic mice respond to TCDD, both in vivo and in organ culture, with altered differentiation of medial epithelial cells. By contrast, in the rat TCDD produces substantial maternal, embryonic, and fetal toxicity, including fetal lethality, with few malformations. In this study the possible effects of maternal toxicity on induction of cleft palate were eliminated by exposure of embryonic rat palatal shelves in organ culture. The shelves were examined for specific TCDD-induced alterations in differentiation of the medial cells. On Gestation Day (GD) 14 or 15 palatal shelves from embryonic F344 rats were placed in organ culture for 2 to 3 days (IMEM:F12 medium, 5% FBS, 0.1% DMSO) containing 0, 1 x 10(-8), 1 x 10(-9), 1 x 10(-10), or 5 x 10(-11) M TCDD. The medial epithelial peridermal cells degenerated on shelves exposed to control media or 5 x 10(-11) M TCDD. Exposure to 10(-10), 10(-9), and 10(-8) M TCDD inhibited this degeneration in 20, 36, and 60% of the shelves, respectively, and was statistically significant at the two highest doses. A normally occurring decrease in [3H]TdR incorporation was inhibited in some GD 15 shelves cultured with 10(-10) and 10(-9) M TCDD. The medial cells of TCDD-exposed shelves continued to express high levels of immunohistochemically detected EGF receptors. The altered differentiation of rat medial epithelium is similar to that reported for TCDD-exposed mouse medial cells in vivo and in vitro. However, in order to obtain these responses, the cultured rat shelves require much higher concentrations of TCDD than the mouse shelves. Thus TCDD induces the same effects at a cellular level in medial epithelium of rats and mice, but cleft palate is not seen in rats because the level required to produce the cellular effects would result in maternal and embryonic toxicity including fetal lethality.     

Colonic Absorption and Bioavailability of the Pentapeptide Metkephamid in the Rat

The concept of delivering systemically active peptide drugs to the colon in order to improve their oral absorption requires reasonable peptide permeability of the large intestinal wall and stability against the activity of the colonic microflora. In addition, the role of hepatic extraction needs to be addressed. In this study the absorption of the pentapeptide metkephamid following single pass perfusion of rat ascending colon was investigated by monitoring its disappearance from the large intestine and simultaneous appearance in the portal vein, the hepatic vein and the aorta. In addition its stability against colonic microflora was tested in vitro using pig caecal contents. Metkephamid was absorbed from the large intestine and appeared in the blood circulation; peptide concentrations in the portal vein increased over-proportionally with increasing perfusate concentrations (0.1 – 4.6 mmol/L) from 0.19 µg/mL ± 0.12 (SD, n = 7) to 31.6 µg/mL + 20.65 (SD, n = 4), respectively, and thus suggesting a saturable transport or metabolism. Concentrations in the hepatic vein were significantly lower than in the portal vein, hepatic extraction ratios were 0.35 ± 0.14, 0.61 ± 0.18 and 0.62 ± 0.28 (SD, n = 4) for 0.1, 0.5 and 1.0 mM metkephamid perfusate concentrations, respectively. In the anaerobic colon metabolism model the degradation half-life of the peptide was 14.9 hours, thus, indicating relative stability in the bacterial environment of the colon. The results of the present study encourage further investigations on colonic delivery of peptide drugs.     

Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol^®, sodium cholate, sodium caprate, hydroxypropyl β-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and P_app of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC_{0-24 h} of ZMR in the lungs following oral administration of PO-SC was 125.22 ± 27.25 ng hr ml^-1 with a C_max of 156.00 ± 24.00 ng/ml reached at 0.50±0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC₅₀ concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.     

提高二膦酸盐类药物口服生物利用度的方法

目的介绍提高二膦酸盐类药物口服生物利用度的方法。方法查阅近年来国内外有关文献,对提高二磷酸盐口服生物利用度的方法进行归纳总结。结果采用加入吸收促进剂、制成生物黏附制剂以及应用前药等方法,均能提高二膦酸盐的口服生物利用度。结论修饰成载体介导的前药是一种提高二膦酸盐口服生物利用度相对安全、有效的方法。随着研究的进一步深入,将会有更简便、实用的方法出现。     

Improving the Oral Bioavailability of Sulpiride by Sodium Oleate in Rabbits

To improve the limited oral bioavailability of sulpiride, a dosage form containing sodium oleate as an absorption enhancer was developed and evaluated using gastric-emptying-controlled rabbits in a cross-over manner. In addition to the known properties of sodium oleate with respect to modifying the permeability of biomembranes, it was found to be capable of improving the physicochemical properties of sulpiride toward a higher lipophilicity (by ion-pair association) and a higher solubility (by micellar solubilization). Nonetheless, the incorporation of sodium oleate with sulpiride as a mixture filled in hard gelatin capsules failed to increase intestinal absorption, whereas the use of enteric capsules, instead of the hard gelatin capsules resulted in a significant increase (P < 0·05) in the oral bioavailability.     

Pharmacokinetics and Oral Bioavailability of Scopolamine in Normal Subjects

The pharmacokinetics and bioavailability of scopolamine were evaluated in six healthy male subjects receiving 0.4 mg of the drug by either oral or intravenous administration. Plasma and urine samples were analyzed using a radioreceptor binding assay. After iv administration, scopolamine concentrations in the plasma declined in a biexponential fashion, with a rapid distribution phase and a comparatively slow elimination phase. Mean and SE values for volume of distribution, systemic clearance, and renal clearance were 1.4 ± 0.3 liters/kg, 65.3 ± 5.2 liters/hr, and 4.2 ± 1.4 liters/hr, respectively. Mean peak plasma concentrations were 2909.8 ± 240.9 pg/ml following iv administration and 528.6 ± 109.4 pg/ml following oral administration. Elimination half-life of the drug was 4.5 ± 1.7 hr. Bioavailability of the oral dose was variable among subjects, ranging between 10.7 and 48.2%. The variability in absorption and poor bioavailability of oral scopolamine indicate that this route of administration may not be reliable and effective.     

口服恩丹西酮胶囊的人体相对生物利用度

用HPLC法测定9名健康志愿者分别口服恩丹西酮（ondancetron）片剂和胶囊各8mg后血浆药物浓度。两药的药动学参数分别为：AUC（0-∞）为194.3±28.0和195.7±33.8g／（L·h）Cmax为25.1±4.9和25．8±44pg／L；Tmax为1．5±0．5和1．4±0．5h。结果说明两制剂具有生物等效性。     

提高难溶性药物口服生物利用度的方法

讨论了影响自胃肠道吸收药物生物利用度的因素，对提高难溶性药物口服生物利用度的方法进行了综述。     

口服用前体脂质体的研究进展

本文对前体脂质体的定义、特点、制备方法、促进口服吸收机理及应用现状等进行综述,旨在为研究前体脂质体提供理论依据.     

Clinical Pharmacokinetics and Relative Bioavailability of Oral Procaterol

The pharmacokinetics and relative oral bioavailability of procaterol, an orally active ₂-adrenergic agonist bronchodilator were evaluated in healthy volunteers. Procaterol was rapidly absorbed after oral administration. Mean plasma procaterol concentration–time profiles and pharmacokinetic parameters for both formulations were essentially superimposable. Following tablet administration, the mean C _max was 358 pg/mL and the corresponding mean t _max was 1.6 hr. Mean renal clearance was 163 mL/min and accounted for approximately one-sixth of the mean apparent oral plasma clearance (988 mL/min). The mean apparent elimination half-life of procaterol was 4.2 hr. Hepatic metabolism appears to be the primary mechanism for elimination of procaterol from the body, and first-pass metabolism may limit systemic bioavailability.     

美欧卡霉素三种口服制剂的相对生物利用度比较

用微生物法测定血药浓度。本文报道6名健康志愿者口服美欧卡霉素干糖浆、片剂及胶囊后的生物利用度比较结果。口服1g上述三种剂型后,其相对生物利用度分别为100%、121%及100%。各主要参数三种剂型间也无显著差异。     

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/ IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.     

Improving the Oral Bioavailability of Sulpiride by a Gastric-retained Form in Rabbits

To improve the limited oral bioavailability of sulpiride, a gastric-retained form was developed and evaluated using gastric-emptying-controlled rabbits. The AUC value after oral administration of sulpiride as an aqueous solution was less than that after oral administration of sulpiride original powder. The dissolution was not important as a rate limiting factor for sulpiride oral absorption. Sulpiride was absorbed predominantly from the upper part of the small intestine of the rabbit. A gastric-retained tablet prepared from Carbopol 934P, with sustained-release characteristics, was found to be suitable for improving and extending the oral bioavailability of sulpiride.     

Meal Composition Effects on the Oral Bioavailability of Indinavir in HIV-Infected Patients

Purpose. To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects. Methods. Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC. Results. All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC_0– decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean C_max was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean t_max was significantly delayed from 1 hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects. Conclusions. Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.