Quantitative Biopharmaceutics Classification System: The Central Role of Dose/Solubility Ratio

PURPOSE: To develop a quantitative biopharmaceutics drug classification system (QBCS) based on fundamental parameters controlling rate and extent of absorption. METHODS: A simple absorption model that considers transit flow, dissolution, and permeation processes stochastically was used to illustrate the primary importance of dose/solubility ratio and permeability on drug absorption. Simple mean time considerations for dissolution, uptake, and transit were used to identify relationships between the extent of absorption and a drug's dissolution and permeability characteristics. RESULTS: The QBCS developed relies on a (permeability, dose/ solubility ratio) plane with cutoff points 2 x 10(-6)-10(-5) cm/s for the permeability and 0.5-1 (unitless) for the dose/solubility ratio axes. Permeability estimates, P(app) are derived from Caco-2 studies, and a constant intestinal volume content of 250 ml is used to express the dose/solubility ratio as a dimensionless quantity, q. A physiologic range of 250-500 ml was used to account for variability in the intestinal volume. Drugs are classified into the four quadrants of the plane around the cutoff points according to their P(app), q values, establishing four drug categories. i.e., I (P(app) > 10(-5) cm/s, q < or = 0.5), II (P(app) > 10(-5) cm/s, q > 1), III (P(app) < 2 x 10(-6) cm/s. q < or = 0.5), and IV (P(app) < 2 x 10(-6) cm/s, q > 1). A region for borderline drugs (2 x 10(-6) < P(app) < 10(-5) cm/s, 0.5 < q < 1) was defined too. For category I, complete absorption is anticipated, whereas categories II and III exhibit dose/ solubility ratio-limited and permeability-limited absorption, respectively. For category IV, both permeability and dose/solubility ratio are controlling drug absorption. Semiquantitative predictions of the extent of absorption were pointed out on the basis of mean time considerations for dissolution, uptake, and transit in conjunction with drug's dose/solubility ratio and permeability characteristics. A set of 42 drugs were classified into the four categories, and the predictions of intestinal drug absorption were in accord with the experimental observations. CONCLUSIONS: The QBCS provides a basis for compound classification into four explicitly defined drug categories using the fundamental biopharmaceutical properties, permeability, and dose/solubility ratio. Semiquantitative predictions for the extent of absorption are essentially based on these drug properties, which either determine or are strongly related to the in vivo kinetics of drug dissolution and intestinal wall permeation.     

Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond

The workshop "Bioequivalence, Biopharmaceutics Classification System, and Beyond" was held May 21-23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.     

甲基斑蝥胺在大鼠胃肠道的吸收动力学

目的研究甲基斑蝥胺(MCD)在大鼠胃及肠道的吸收动力学特征。方法采用封闭灌注技术进行原位胃灌注吸收研究,在体循环法考察小肠全肠段吸收,采用单向肠灌流技术进行不同肠段吸收研究,建立HPLC法测定MCD的浓度,考察MCD大鼠胃肠吸收特征及吸收机制。结果 116.34mg·L~(-1)MCD在十二指肠、空肠、回肠、结肠及胃中的吸收速率常数(K_a)分别为(0.0635±0.0091)、(0.0687±0.0008)、(0.0315±0.0009)、(0.0399±0.0009)和(0.0033±0.0001)min~(-1),不同药物浓度59.55、116.34、204.15mg·L~(-1)时胃及空肠中的K_a分别为(0.0031±0.0001)、(0.0033±0.0001)、(0.0031±0.0001)min~(-1)及(0.0667±0.0010)、(0.0687±0.0008)、(0.0705±0.0011)min~(-1);在空肠不同pH值(5.0,6.2,7.4)时K_a分别为(0.0801±0.000 9)、(0.0783±0.0009)、(0.0758±0.0009)min~(-1)。MCD在胃中吸收很弱;在空肠、十二指肠、结肠和回肠中均有一定吸收,在空肠吸收最好,在肠中吸收呈一级动力学过程,吸收机制为被动扩散。MCD溶液浓度及pH值对其肠吸收速率无显著影响(P>0.05)。结论 MCD属于生物药剂学分类系统Ⅰ类药物。     

Biopharmaceutics classification and intestinal absorption study of apigenin

The aim of the study was to characterize the biopharmaceutics classification system (BCS) category of apigenin (AP) using intrinsic dissolution rate (IDR) and rat intestinal permeability, and to investigate the intestinal absorption mechanism of AP in rats. In the present investigation, equilibrium solubility and intrinsic dissolution rate (IDR) of AP were estimated in phosphate buffers. Effective intestinal permeability (P(eff)) of AP was determined using single-pass intestinal perfusion (SPIP) technique in four segments (duodenum, jejunum, ileum and colon) of rat intestine at three concentrations (10, 50 and 100μg/ml). The aqueous solubility of AP in tested phosphate buffers was very poor with maximum solubility of 2.16μg/ml at pH 7.5. The IDR of AP was very low with a value of 0.006mg/min/cm(2). The minimum and maximum P(eff)s determined by SPIP were 0.198×10(-4) and 0.713×10(-4)cm/s at jejunum and duodenum site, respectively. In addition, the concentration-dependent permeability behavior was observed in the duodenum and jejunum, which suggested that AP was transported by both passive and active carrier-mediated saturable mechanism in these two intestinal segments. However, the observed concentration-independent permeability behavior in ileum and colon indicated primarily passive transport mechanism of absorption of AP in the last two intestinal segments. AP was classified as class II drug of the BCS due to its low solubility and high intestinal permeability. AP could be well absorbed in the whole intestine with the main absorption site at duodenum. The absorption of AP in four intestinal segments exhibited different transport mechanisms.     

Intestinal permeability and its relevance for absorption and elimination

Human jejunal permeability (P_eff) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P_eff are often based on multiple parallel transport processes. Site-specific jejunal P_eff cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P_eff > 1.5 x 10^–4 cm s^–1 will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal P_eff for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.     

Rate-limiting barriers to intestinal drug absorption: A review

The intestinal epithelium is composed of several structures that could serve as barriers to the transfer of drugs from the GI lumen to the systemic circulation. An aqueous stagnant layer that overlies the apical membrane and the subepithelial blood flow are potential barriers to the absorption of drugs that readily penetrate the absorbing cell of the epithelium. The apical, basal, and basement membranes are potential barriers to the absorption of less permeable drugs. The cytoplasm of the absorbing cell is a relatively thick barrier that must also be traversed. While the location and structure of these potential barriers are well known, those barriers that are operative and the kinds of molecules for which they are operative are not known. The structure and permeability properties of the potential barriers are considered, along with the roles of the paracellular pathway and countercurrent exchange in the villus circulation.     

药物的肠吸收与处置研究进展

对近几年药物肠吸收与处置方面的研究进展进行了综述。包括:特定部位吸收、代谢的认识和利用,与药物首过效应有关的肠壁外泌及代谢作用的介绍,促进药物肠道吸收的方法及常用研究模型的比较。     

Blood flow in intestinal absorption models

Up to the present, ten models have been proposed or applied to analyze the relationship between blood flow and intestinal absorption. The conceptions of these models and their basic and final equations are described. In addition, their relationship to the first-order rate constants used in the models not explicitly including the blood flow rate is elucidated. Usually a curvilinear (concave curvature) relationship between the blood flow rate and the absorption rate is predicted by the models. This similarity of the curves is the reason that in many cases several models are compatible with the experimental data.     

吸收促进剂对蚓激酶肠道吸收的影响

目的研究蚓激酶(YJM-I)和吸收促进剂合用时在大鼠肠道各段的吸收特点，寻找YJM-I经肠道吸收的最佳位置和考察吸收促进剂对YJM-I在肠道吸收过程中的影响。方法采用体外扩散池法、十二指肠部位直接给药、在体循环灌流及肠段原位结扎等方法对荧光标记的FITC-YJM-I在大鼠肠道的吸收情况进行了研究。结果十二指肠部位给药后的药代动力学和药效学评价结果显示YJM-I药物分子可被大鼠肠道吸收进入血液循环并保持生物学活性，但其绝对生物利用度较低。体外肠黏膜通透性试验及体内肠段吸收试验结果显示部分吸收促进剂表现出良好的促进YJM-I肠道吸收的作用。十二指肠、空肠和回肠段体外肠黏膜通透性均显示了相似的吸收促进剂作用强弱趋势： 1%壳聚糖>1%去氧胆酸钠>1% Na₂EDTA>1%十二烷基硫酸钠>1%辛酸钠>1%泊洛沙姆>1%羟丙基-β-环糊精。而在体内十二指肠部位给药则显示的强弱顺序为： 2.5%去氧胆酸钠>2.5% Na₂EDTA>2.0%壳聚糖>2.5%十二烷基硫酸钠>2.5%辛酸钠>2.5%泊洛沙姆>2.5%羟丙基-β-环糊精。结论吸收促进剂能有效地增加YJM-I肠道吸收程度，其中具有生物黏附作用的壳聚糖有望成为YJM-I肠道吸收的良好促进剂。     

植物甾醇肠道吸收研究进展

植物甾醇是一类具有降胆固醇作用的天然活性物质,作为食品添加剂在世界各国广泛使用,在我国也被批准为新资源食品。鉴于植物甾醇的降胆固醇作用与其肠道吸收过程密切相关,本文针对该过程关键蛋白(NPC1L1、ABCG5/G8、ACAT、ApoB-48、MTP)进行综述,探讨植物甾醇在肠道对胆固醇吸收的影响。     

大鼠在体单向肠灌流法对核黄素肠吸收的研究

目的：研究核黄素在大鼠肠道的在体吸收情况。方法应用大鼠在体肠灌流技术中的重量法研究核黄素在大鼠的十二指肠、空肠、回肠的吸收情况,用高效液相色谱法测定肠灌流液中核黄素的含量,计算核黄素的有效渗透系数（Pef）及药物吸收速率常数（Ka ）。结果核黄素在大鼠各肠段的 Pef（×10－4 cm·s －1）按十二指肠、空肠、回肠顺序依次分别为1.002±0.630、0.818±0.386、0.796±0.372;Ka （×10－3 s －1）依次为1.114±0.625、0.905±0.452、0.873±0.369。结论核黄素在大鼠肠段不同部位吸收存在差异,核黄素在十二指肠的吸收显著高于空肠和回肠段。     

A rule of unity for human intestinal absorption 3: Application to pharmaceuticals

The rule of unity is based on a simple absorption parameter, Π, that can accurately predict whether or not an orally administered drug will be well absorbed or poorly absorbed. The intrinsic aqueous solubility and octanol–water partition coefficient, along with the drug dose are used to calculate Π. We show that a single delineator value for Π exist that can distinguish whether a drug is likely to be well absorbed (FA ≥ 0.5) or poorly absorbed (FA < 0.5) at any specified dose. The model is shown to give 82.5% correct predictions for over 938 pharmaceuticals. The maximum well‐absorbed dose (i.e. the maximum dose that will be more than 50% absorbed) calculated using this model can be utilized as a guideline for drug design and synthesis.     

Determination of site of absorption of propranolol in rat gut using in situ single-pass intestinal perfusion

Previously, permeability and site of intestinal absorption of propranolol have been reported using the Ussing chamber. In the present study, the utility of Single-Pass Intestinal Perfusion to study permeability and site of intestinal absorption of propranolol was evaluated in rats. Drug permeability in different regions of rat intestine viz. duodenum, jejunum, ileum and colon was measured. Propranolol (30 μg/ml) solution was perfused in situ in each intestinal segment of rats. Effective permeability (Peff) of propranolol in each segment was calculated and site of absorption was determined. The Peff of propranolol in rat duodenum, jejunum, ileum and colon was calculated to be 0.3316×10(-4) cm/s, 0.4035×10(-4)cm/s, 0.5092×10(-4) cm/s and 0.7167×10(-4) cm/s, respectively. The above results suggest that permeability of propranolol was highest through colon compared to other intestinal sites, which is in close agreement to that reported previously. In conclusion, in situ single pass intestinal perfusion can be used effectively to study intestinal permeability as well as site of intestinal absorption of compounds in rats.     

马尼地平磷脂复合物的表征及肠吸收研究

目的：对马尼地平磷脂复合物进行表征,并考察其体外肠吸收特性。方法：采用紫外分光光度法、差示扫描量热分析法、溶解度法和溶出度测定法对马尼地平磷脂复合物性质进行表征;通过离体外翻肠囊模型考察马尼地平在不同肠段的吸收特性。结果：与原药及原药-磷脂物理混合物比较,磷脂复合物的溶解度、溶出度、油/水分配系数、紫外吸收均有不同程度的改变,磷脂复合物在各肠段部位的转运速率V_t和表观渗透系数P_app均大于原药,其中在空肠的吸收均显著强于其他部位（P<0.01）。结论：马尼地平复合磷脂后,其溶解度、溶出度、肠吸收明显改善,马尼地平磷脂复合物将有利于提高药物的生物利用度。     

药物肠道吸收研究方法

药物在肠道内的吸收程度和吸收特征是影响口服药物生物利用度的重要因素。肠道吸收研究可以预测影响药物在肠道吸收的机制与因素,研究方法主要包括体内法（invivo）、在体法（insitu）、体外法（invitro）等。就目前药物小肠吸收的研究方法及其特点进行综述。     

肠道转运蛋白在药物吸收中的重要作用

1引言 分子生物学和遗传基因学的发展使得对载体介导膜转运的认识提高到了分子基因水平.转运蛋白的存在在很大程度上决定了某些药物向靶部位及非靶部位的分布特征.     

Predictive approaches to increase absorption of compounds during lead optimisation

Introduction: Complex physicochemical and biological processes influence the oral absorption of a drug molecule. Consideration of these processes is an important activity during the optimisation of potential candidate molecules.

Areas covered: The authors review the applications of physicochemical and structural requirements for intestinal absorption. Furthermore, they provide examples of how to aid the lead optimisation process through improvement of solubility and permeability.

Expert opinion: The physicochemical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The size of the molecule also affects both solubility and permeability. Several models can be used to estimate oral absorption from chemical structure or from measured physicochemical properties. Thus, logD–cMR model, the ‘golden triangle' model, Abraham solvation equations and absorption potential can be used as tools in the lead optimisation process. Measured values of solubility and permeability greatly improve the estimation of in vivo oral absorption of compounds. However, it is important to appreciate that predictions of oral absorption may be confounded by the involvement of active transporters in the gut which may either increase (e.g., active uptake) or decrease (e.g., efflux) the absorption of drug molecules. To evaluate the first-pass metabolism, in vitro clearance measurements using liver microsomes can be used in physiologically based models for the estimation of bioavailability. The general tools discussed in this review are based on the physicochemical property assessment of compound libraries and they help design compounds that occupy desirable property space with increased likelihood of good oral absorption.