在体皮肤药代动力学研究方法

在体皮肤药代动力学研究可以直接反应出药物在皮内的变化规律,是研究外用药及系统用药后,药物在靶部位作用强度、量-效关系、代谢规律的直接手段,有助于制定合理的给药剂量及间隔,为合理用药提供依据.实验的模型和方法主要包括胶带黏贴试验、皮肤微透析、吸疱试验、组织活检、琼脂凝胶板试验及光谱分析法等.     

在体皮肤药代动力学研究方法

在体皮肤药代动力学研究可以直接反应出药物在皮内的变化规律,是研究外用药及系统用药后,药物在靶部位作用强度、量-效关系、代谢规律的直接手段,有助于制定合理的给药剂量及间隔,为合理用药提供依据.实验的模型和方法主要包括胶带黏贴试验、皮肤微透析、吸疱试验、组织活检、琼脂凝胶板试验及光谱分析法等.     

微透析技术在皮肤药代动力学研究中的应用进展

经皮微透析是一种独特的在体取样技术,可测定真皮及皮下组织中游离药物浓度,是获得以真皮为作用靶位的药物实时动力学数据的首选方法.在局部皮肤屏障异常或存在皮损的情况下,进行药物经皮渗透性研究方面具有独特的优势.在过去的几十年里该技术发展迅速并被证明是一种用途广泛、安全、有效的皮肤外用制剂药代动力学与药效学研究工具.但该方法的重现性、探针植入与由此引起的组织损伤之间的确切关系,以及如何更简便地适用于脂溶性药物的研究等方面仍需深入研究.     

微透析与经皮药代动力学

近20年来,微透析技术在皮肤方面的应用日趋广泛和深入。微透析技术是一种膜取样技术,并需要连接分析装置。这一技术最初用于神经生理学研究,用于药物经皮渗透及皮肤中药物浓度的研究中,称为经皮微透析。就近10年来微透析技术在经皮药代动力学方面研究中的应用作一综述。     

微透析与经皮药代动力学

近20年来，微透析技术在皮肤方面的应用日趋广泛和深入。微透析技术是一种膜取样技术。并需要连接分析装置。这一技术最初用于神经生理学研究，用于药物经皮渗透及皮肤中药物浓度的研究中，称为经皮微透析。就近10年来微透析技术在经皮药代动力学方面研究中的应用作一综述。     

伊曲康唑的抗真菌性及药代动力学

伊曲康唑是三唑类抗真菌药物，它具有高亲脂性，此特性在很大程度上决定了它的药代动力学。在人类其特点是：口服吸收好，组织分布广，组织中的浓度比血浆中高很多倍。在一些感染组织中其浓度要比血浆中维持的时间长得多。伊曲康唑不干优哺乳动力物谢酶，减少了与之同时服用的药物间相互作用的危险性。体外试验及动物模型证明伊曲康唑具有抗真菌谱广、疗效好的特点。     

多药耐药基因多态性与异维A酸人体药代动力学差异关联性研究

目的研究多药耐药基因MDR1基因多态性对异维A酸人体药代动力学(药动学)的影响。方法 21例健康男性受试者单次口服40 mg异维A酸胶丸,提取外周血基因组DNA采用等位基因特异扩增法(allele-specificamplification,ASA-PCR)对MDR1外显子(exon)12(C1236T)、exon21(G2677T/A)、exon26(C3435T)位点进行基因分型检测;高效液相色谱-串联质谱法(HPLC/MS)分析受试者异维A酸血药浓度并计算相关药动学参数,比较不同基因型药动学参数差异。结果 MDR1exon12(C1236T)的不同基因型异维A酸的体内某些药动学参数有差异。与野生型组相比,变异型组Cmax、Tmax有所增加,但差异无统计学意义(P值分别为0.057、0.252);AUC 0～60显著提高(P=0.049)、T1/2及MRT明显缩短(P值分别为0.011、0.035)。MDR1exon21(G2677T/A)的不同基因型异维A酸的体内各项药动学参数差异无统计学意义。MDR1 exon26(C3435T)参数T1/2、MRT、AUC 0～60在杂合型组与变异型组之间差异无统计学意义,变异型组Cmax有所增加,差异无统计学意义;变异型组Tmax显著小于杂合型组(P=0.03)。结论MDR1 C1236T变异型组体内异维A酸吸收略有增多,T1/2、MRT缩短,异维A酸的体内代谢明显加快。虽然MDR1G2677T/A及MDR1 C3435T之间存在显著遗传连锁不平衡关系,且对P糖蛋白(P-gp)的功能影响较大,但本研究结果显示这两个位点基因突变对异维A酸的体内过程影响不显著。     

健康志愿者单次口服国产泛昔洛韦片后的药代动力学

目的：研究我国男性健康志愿者单次口服国产泛昔洛韦片后的药代动力学行为,并与英国产同类制剂作比较,求得相对生物利用度。方法：８例男性健康志愿者以四阶优化丁方设计分别交叉单次口服英国产及三个剂量的国产泛昔洛韦片,在０～２４ｈ内１１个时间点采集血浆及分段尿液,高效液相法测定血、尿中的喷昔韦浓度,并用３Ｐ８７程序计算药代动力学参数和相对生物利用度。结果：口服泛昔洛韦片后,药物在体内的动力学表现为二室模型,三个受试剂量的药代动力学参数与英国产制剂及文献数据基本一致。结论：受试药与对照药的药代动力学基本相同,受试药的相对生物利用度平均值为１１０．８７％。     

皮肤微透析技术研究新进展

皮肤微透析技术是应用半透膜两侧溶质被动自由弥散原理 ,动态地监测真皮组织间液内源性或外源性物质浓度的新技术。本文介绍了该技术的原理和方法 ;综述了近年在皮肤病理生理学、皮肤药代动力学等领域的新进展     

An ex vivo human skin model for studying skin barrier repair

In the studies described in this study, we introduce a novel ex vivo human skin barrier repair model. To develop this, we removed the upper layer of the skin, the stratum corneum (SC) by a reproducible cyanoacrylate stripping technique. After stripping the explants, they were cultured in vitro to allow the regeneration of the SC. We selected two culture temperatures 32°C and 37°C and a period of either 4 or 8 days. After 8 days of culture, the explant generated SC at a similar thickness compared to native human SC. At 37°C, the early and late epidermal differentiation programmes were executed comparably to native human skin with the exception of the barrier protein involucrin. At 32°C, early differentiation was delayed, but the terminal differentiation proteins were expressed as in stripped explants cultured at 37°C. Regarding the barrier properties, the SC lateral lipid organization was mainly hexagonal in the regenerated SC, whereas the lipids in native human SC adopt a more dense orthorhombic organization. In addition, the ceramide levels were higher in the cultured explants at 32°C and 37°C than in native human SC. In conclusion, we selected the stripped ex vivo skin model cultured at 37°C as a candidate model to study skin barrier repair because epidermal and SC characteristics mimic more closely the native human skin than the ex vivo skin model cultured at 32°C. Potentially, this model can be used for testing formulations for skin barrier repair.     

Pharmacodynamics and dermatopharmacokinetics of betamethasone 17-valerate: assessment of topical bioavailability

Background  The bioavailability of most topically delivered drugs is difficult to quantify, but is generally believed to be very low. With the exception of the vasoconstrictor assay for corticosteroids, no methodology to quantify the rate and extent of drug delivery to the skin has been validated. Recent research has examined the dermatopharmacokinetic (DPK) technique, which is based on stratum corneum (SC) tape-stripping.
Objective  To compare the in vivo bioavailability of different topical formulations of betamethasone 17-valerate (BMV) using the vasoconstrictor assay and the DPK method.
Methods  BMV was formulated in different vehicles and the drug concentration was adjusted to either (i) equal thermodynamic activity, or (ii) a range of values up to that corresponding to 80% of maximum thermodynamic activity. Vasoconstriction, an accepted and widely used method to determine bioavailability and bioequivalence of topical steroids, was quantified with a chromameter over 24 h post-removal of the formulation. Drug uptake into the SC was assessed by tape-stripping.
Results  BMV at the same thermodynamic activity in different vehicles provoked similar skin blanching responses, while DPK profiles distinguished between the formulations. Further, skin blanching responses and drug uptake into the SC clearly depended upon the absolute BMV concentration applied. However, while the saturable nature of the pharmacodynamic response was clear, the tape-stripping method distinguished unequivocally between the different formulations and different concentrations.
Conclusions  The DPK approach offers a reliable metric with which to quantify transfer of drug from the vehicle to the SC, and may be useful for topical bioavailability and bioequivalence determinations.     

Bioavailability of clobetasol propionate-quantification of drug concentrations in the stratum corneum by dermatopharmacokinetics using tape stripping.

The concentration of clobetasol propionate in the stratum corneum after application of three different formulations was determined, quantifying the influence of the formulations on the bioavailability of the drug. The stratum corneum was sampled by tape stripping. The concentrations of clobetasol propionate were determined quantitatively by HPLC. After application of Clobetasol Propionate Cream USP, 0.05%, and Temovate Cream, 0.05%, identical amounts of the drug were found in the stratum corneum, whereas after application of Temovate epsilon Emollient, 0.05%, the quantity was clearly decreased. From results obtained measuring the drug concentration in the adjacent sites of the skin where the creams had not been applied, it became clear that clobetasol propionate in Temovate epsilon Emollient, migrated to a large extent in the lateral direction. This explains the lower concentration measured for this formulation in the skin areas where the cream had been applied. In general, a lateral distribution of the applied drug must be taken into account when positioning the application areas on the forearm.