Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit,Monkey, and Dog Intestine and Human Drug Absorption

The in vitro permeabilities of Caco-2 monolayers and permeabilities in tissue sections from colon of monkey, rabbit, and dog were compared using a series of compounds. The selected compounds differed in their physicochemical properties, such as octanol/water partition coefficient, water solubility, and molecular weight. Their structure included steroids, carboxylic acids, xanthins, alcohols, and polyethylene glycols. A linear permeability relationship was established between Caco-2 and colon tissue from both rabbit and monkey. The results suggest that Caco-2 is twice as permeable as rabbit and five times as permeable as monkey colon. However, no clear relationship could be established between Caco-2 monolayers and dog colon permeability. A relationship between permeability in Caco-2 monolayers and human absorption was found. The results suggest that within certain limits, permeability of Caco-2 monolayers may be used as a predictive tool to estimate human drug absorption.     

乳液聚合型品红成色剂的应用性能

测试了3种新型L-品红成色剂的应用性能。结果表明：与母体品红成色剂相比，L-品红成色剂能显著地减少在蓝光区的有害吸收；与工业用油溶性品红成色剂Ns相比，L-品红成色剂的一些照相性能更加优越。     

A method for calculating the mean absorption time of drugs undergoing reversible and first-pass metabolism

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.     

A Novel Extravascular Input Function for the Assessment of Drug Absorption in Bioavailability Studies

Purpose. Flexible parametric models describing the input process after extravascular drug administration are needed for the assessment of absorption rate and the use of population methods in bioavailability and bioequivalence studies. Methods. The oral concentration-time curve modeled as the product of the input and disposition function in the Laplace domain was obtained by numerical inversion methods for parameter estimation. The utility of the inverse Gaussian input density was examined using bioavailability data of an extended-release dosage form. Measures of rate of absorption and the cumulative absorbed amount profile were defined in terms of the estimated model parameters. Results. Accurate estimation of absorption parameters was achieved by simultaneous fitting of the extravascular and intravascular data (describing the latter by a triexponential function). The new input function allowed a direct estimation of both extent of absorption and mean absorption time. Conclusions. The findings suggest that the inverse Gaussian density is a useful input function. Its flexibility may reduce the effect of model misspecification in parameter estimation. All parameters can be readily interpreted in terms of the absorption process.     

双氯灭痛药膜体外透皮速率的实验研究

作者选择乙基纤维素、聚乙烯醇等高分子材料制成涂膜剂，用大鼠皮进行双氯灭痛药膜的体外透皮速率测定。结果表明，氮酮与丙二醇可以促进药物渗透。不同的高分子材料可影响药物的扩散与释放，从而影响其透皮速率。与无膜无促透剂处方相比，药物在乙基纤维素中的透皮速率没有增加，在聚乙烯醇膜中的透皮速率有显著增加。     

免疫反应在实验性游离型腰椎间盘突出自然吸收中的意义

目的：通过检测CD3和IgG在实验性游离型腰椎间盘突出自然吸收中的表达，探讨腰椎间盘突出后能否自然吸收及其可能的吸收机制。方法：将25只成年狗平均分成5组，从L2/3切取髓核组织，置于L5处的硬脊膜外，于术后2，4，6，8，12周，取动物标本以及正常部位的髓核组织，用CD3抗体和抗IgG进行免疫组化检测。结果：约30%的标本局部为脂肪组织，54%的标本局部硬脊膜与骨粘连，16%的标本既无粘连也无脂肪，免疫组化测定显示，随着时间的推移，CD3^ 细胞的浸润程度呈递减趋势，而IgG沉积的分布程度呈递增趋势，正常髓核无CD3^ 细胞浸润，IgG沉积分布极少。结论：在椎管内，狗游离的髓核组织8-12周后可部分或全部自然吸收，其吸收机制是机体自身免疫反应的结果。     

Small-dose oral iron absorption test in anaemic and non-anaemic elderly hospitalized patients

Abstract: The small-dose (20 mg) oral iron absorption test (OIAT) was performed in 76 hospitalized elderly patients and 30 healthy adults. Of the elderly patients, 34 were considered as iron deficient (serum ferritin level <20 μg/L) of whom 23 were anaemic and 11 not anaemic, 21 had the anaemia of chronic disorders (ACD) and another 21 were non-anaemic patients with a normal serum ferritin level. There was a significant inverse correlation between the serum ferritin level as a measure of iron store and the maximum increase in serum iron during a 3-h test (C_max), in the elderly as well as in the healthy adult group. A decision limit of 80 μg/dL for C_max is a good discriminant between absent (serum ferritin <20 μg/L) and adequate body iron stores. Sixty-eight per cent of the patients with a serum ferritin level <20 μg/L but virtually none of the ACD patients, non-anaemic elderly inpatients with normal serum ferritin levels and healthy adults had a C_max level >80 μg/L. Although further investigation is needed before the OIAT can be recommended as a valuable test for evaluating iron absorption, predicting mild iron deficiency and differentiating between different categories of anaemia, it seems worthwile that more effort should be done to validate this simple and safe test.     

Plasma concentrations and bioavailability of propranolol by oral, rectal, and intravenous administration in man

Eight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2.2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration-time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two-fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.     

Effect of concomitant food intake on absorption kinetics of fenoldopam (SK&F 82526) in healthy volunteers

Summary Eight healthy volunteers participated in an open crossover study to assess the effect of a standardised meal on the systemic availability of a single oral dose of fenoldopam mesylate 100 mg. Subjects were studied on four separate occasions, twice fasting and twice fed in randomised, balanced order. Plasma and urine samples were obtained before and at regular intervals up to 25 h post dose. Measurement of fenoldopam (SK&F 82526) and its 8-sulphate metabolite (SK&F 87782) were by means of HPLC-EC analysis. Area under the plasma concentration time curve (AUC) and maximum detected plasma concentration (C_max) for fenoldopam and SK&F 87782 were significantly reduced whereas time to maximum concentration was significantly increased with food. Using AUC's for fenoldopam and SK&F 87782, mean relative bioavailabilities were 35% and 81% respectively under fed compared with fasting conditions. Twenty-four hour excretion of fenoldopam was significantly reduced with food, but excretion of SK&F 87782 was apparently unchanged. Mean relative bioavailabilities calculated from these data were 83% and 86% respectively. Relatively large inter-subject variability in AUC and C_max were seen, but intra-subject variability was not marked. Mild symptoms associated with vasodilation were reported on all study days.     

A New Method for Estimating Dermal Absorption from Chemical Exposure. 3. Compared with Steady-State Methods for Prediction and Data Analysis

Purpose. This paper compares unsteady-state and steady-state methods for estimating dermal absorption or analyzing dermal absorption data. The unsteady-state method accounts for the larger absorption rates during short exposure times as well as the hydrophilic barrier which the viable epidermis presents to lipophilic chemicals. Methods. Example calculations for dermal absorption from aqueous solutions are presented for five environmentally relevant chemicals with molecular weights between 50 and 410 and log₁₀K_ow between 0.91 and 6.8: chloromethane, chloroform, chlordane, 2,3,7,8-TCDD, and dibenz(a,h)anthracene. Also, the new method is used to evaluate experimental procedures and data analyses of in vivo and in vitro permeation measurements. Results. In the five example cases, we show that the steady-state approach significantly underestimated the dermal absorption. Also, calculating permeability values from cumulative absorption data measured for exposure periods less than 18 times the stratum corneum lag time will overestimate the actual permeability. Conclusions. In general, steady-state predictions of dermal absorption will underestimate dermal absorption predictions which consider unsteady-state conditions. Permeability values calculated from data sets which include unsteady-state data will be incorrect. Strategies for analyzing in vitro diffusion cell experiments and confirming steady state are described.