Human Oral Absorption Research Articles

In Vitro Dissolution/Permeation System to Predict the Oral Absorption of Poorly Water-Soluble Drugs: Effect of Food and Dose Strength on It

The aim of the present work was to confirm the usefulness of the dissolution/permeation system (D/P system) in the estimation of human oral absorption of poorly water-soluble drugs. The D/P system, which can simultaneously evaluate drug absorption processes, dissolution and permeation, can predict the oral absorption of poorly water-soluble drugs in fasted and fed humans, with a correlation between in vivo oral absorption (% of absorbed) and in vitro permeated amount (% of dose/2 h) in the D/P system. The oral absorption (fraction of absorbed dose, %) of poorly water-soluble drugs in the fasted and fed states was predicted using the D/P system. The effect of food on the oral absorption of various drugs estimated by the D/P system significantly correlated with clinical data (correlation coefficient: r(2)=0.924). Moreover, the proportion of oral absorption of cilostazol was predicted to decrease with an increase in its dose strength, which significantly correlated with in vivo human absorption. Consequently, the D/P system was demonstrated to be a useful in vitro system for prediction of the oral absorption of poorly water-soluble drugs.

Importance of Physicochemical Properties for the Design of New Pesticides

The physicochemical properties of candidate compounds play important roles in the design of new pesticides. Pesticides must be absorbed by pests, be transported to the target site, and then interact with proteins. Hydrophobicity is very important for these processes. Log P, where P is the partition coefficient in the 1-octanol/water system, is commonly used as a hydrophobic descriptor and correlates with membrane permeation and transport. It was recently reported that permeability by the parallel artificial membrane permeation assay (PAMPA) could be used to predict human oral absorption of passively transported compounds. PAMPA, which is a rapid high-throughput screening system, may be useful to predict pesticide absorption because PAMPA permeability can be calculated using log P and other parameters. Electronic and structural properties as well as hydrophobicity are important factors for protein-ligand interaction. To show the importance of physicochemical properties, the classic QSAR and CoMFA of neonicotinoids and prediction of bioavailability of pesticides in terms of membrane permeability in comparison with drugs are described.

3D-pharmacophore model based virtual screening to identify dual-binding site and selective acetylcholinesterase inhibitors

The formation of β-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer’s disease (AD). Interestingly, research on acetylcholinesterase (AChE) enzyme has increased due to findings supporting this enzyme involvement in the β-amyloid peptide fibril formation during AD pathogenesis. In this investigation, chemical features based 3D pharmacophore models were developed from structurally diverse xanthostigmine derivatives, known inhibitors of AChE enzyme, using 3D-QSAR pharmacophore generation module in Discovery Studio2.5 (DS2.5). The constructed pharmacophore models for AChE inhibitors was further cross-validated using test set and Cat-Scramble methodology. The best quantitative pharmacophore model Hypo1, was used for screening the chemical databases of small compounds including Specs, NCI, and IBScreen, to identify the new compounds that are presumably able to act as dual-binding site AChE inhibitors. The screened virtual hits were then subjected to the Lipinski’s rule of five, blood–brain barrier (BBB), PSA, LogS, percent human oral absorption, and toxicity analysis. Finally, 32 compounds were identified as potential leads against AChE enzyme, showing good estimated activities and promising ADMET properties. Molecular docking of these compounds using FlexX software showed catalytic and peripheral anionic binding site interactions, so called dual binding of the AChE enzyme. Docking study was also performed on butyrylcholinesterase in order to understand the compound selectivity. This study may assist in the discovery and design of novel dual binding site and selective AChE inhibitors with potent inhibitory activity.

Biomimetic chromatographic analysis of selenium species: Application for the estimation of their pharmacokinetic properties

The retention behavior of selenites, selenates, seleno-DL-methionine, selenocystine, selenocystamine, selenourea, dimethyl selenide, and dimethyl diselenide was investigated by means of biomimetic liquid chromatography. For this purpose, two immobilized artificial membrane (IAM) columns, namely, IAM.PC.DD2 and IAM.PC.MG, and two immobilized plasma protein columns, human serum albumin (HSA) and alpha(1)-acid glycoprotein (AGP) columns, were employed using different mobile phase conditions in respect to pH and buffer composition. In general, satisfactory interrelations between retention factors obtained with the two IAM stationary phases and HSA/AGP columns were obtained. Large differences were observed between biomimetic retention factors and octanol-water logD values, since the latter fail to describe electrostatic interactions. In contrast, despite the column diversity, the net retention outcome on all four biomimetic columns was quite similar, especially in the presence of phosphate-buffered saline, which by its effective shielding alleviates the differences between the stationary phases. Of the two IAM columns, IAM.PC.DD2 showed better performance when compared with HSA and AGP columns as well as to octanol-water partitioning. Biomimetic chromatographic indices were further used to estimate the percentage of human oral absorption and plasma protein binding of the eight selenium species investigated, according to equations previously reported in the literature. The estimated values of human oral absorption imply moderate absorption only for dimethyl diselenide, which also may exhibit considerable plasma protein binding. Moderate affinity for plasma proteins should also be expected for dimethyl selenide and selenocystamine.

ChemInform Abstract: In silico Prediction of Human Oral Absorption Based on QSAR Analyses of PAMPA Permeability.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Metabolism and Excretion of Anacetrapib, a Novel Inhibitor of the Cholesteryl Ester Transfer Protein, in Humans

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (approximately 2 microM equivalents of [(14)C]anacetrapib) was achieved approximately 4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing <or=14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.

In silico Prediction of Human Oral Absorption Based on QSAR Analyses of PAMPA Permeability

The parallel artificial membrane permeation assay (PAMPA) was developed as a model for the prediction of transcellular permeation in the process of drug absorption. Our research group has measured the PAMPA permeability of peptide-related compounds, diverse drugs, and agrochemicals. This work led to a classical quantitative structure-activity relationship (QSAR) equation for PAMPA permeability coefficients of structurally diverse compounds based on simple physicochemical parameters such as lipophilicity at a particular pH (log P(oct) and |pKa-pH|), H-bond acceptor ability (SA(HA)), and H-bond donor ability (SA(HD)). Since the PAMPA permeability of lipophilic compounds decreased with their apparent lipophilicity due to the unstirred water layer (UWL) barrier on membrane surfaces and to membrane retention, a bilinear QSAR model was introduced to explain the permeability of a broader set of compounds using the same physicochemical parameters as those used for the linear model. We also compared PAMPA and Caco-2 cell permeability coefficients of compounds transported by various absorption mechanisms. The compounds were classified according to their absorption pathway (passively transported compounds, actively transported compounds, and compounds excreted by efflux systems) in the plot of Caco-2 vs. PAMPA permeability. Finally, based on the QSAR analyses of PAMPA permeability, an in silico prediction model of human oral absorption for possibly transported compounds was proposed, and the usefulness of the model was examined.

Measurement and Prediction of Oral Absorption

After defining oral absorption, this review article summarizes the influence of different physiological and physicochemical parameters on oral absorption explained according to the situation at BayerScheringPharma. Along the optimization process in industries, prediction of oral absorption is exemplified. In silico prediction of oral absorption in early stages of research is highlighted with three examples, i.e., a classification algorithm, a single parameter prediction, and a linear free-energy relationship. In vitro prediction of permeation using Caco-2 cell layers and physicochemical modeling is exemplified. The influence of solubility is shown by a concrete example, in particular, using physiologically based pharmacokinetic (PBPK) modeling and physicochemical parameters. For later stages, optimization examples of in vivo animal models stress the importance of excellent in vivo data and in vivo/in vivo correlations for the prediction of human oral absorption from animal experiments.

The usefulness of an artificial membrane accumulation index for estimation of the bioconcentration factor of organophosphorus pesticides

The bioconcentration factor ( BCF) is an important ecotoxicological parameter that describes the accumulation of chemicals in organisms. As many studies have reported, log BCF has good correlation with the logarithm of the 1-octanol/water partition coefficient, log P oct, for chemicals that have log P oct values below about 6 and are not significantly metabolized in organisms. In this study we measured a membrane accumulation index, that is, the membrane partition ( P M) of organophosphorus pesticides using the parallel artificial membrane permeation assay (PAMPA) to clarify whether this index is useful for the estimation of BCF. As a result, log P M had good correlation with log P oct except for iprobenfos and edifenphos. Furthermore, log BCF in five kinds of fish, especially male guppy correlated better with log P M than log P oct. The results indicate that log P M is a better index for predicting log BCF than log P oct. We have already reported that PAMPA permeability coefficients could predict human oral absorption of compounds, including hydrophobic chemicals and agrochemicals. Since it is expected that both human oral absorption and BCF can be estimated simultaneously using PAMPA, PAMPA is useful for exposure estimation to humans of chemicals in the environment.

Permeability evaluation of peptidic HCV protease inhibitors in Caco-2 cells-correlation with in vivo absorption predicted in humans

The permeability of six peptidic hepatitis C virus (HCV) protease inhibitors, with molecular weights ranging from 500 to 780, was examined in the Caco-2 cell system. All six compounds permeated the cells transcellularly; paracellular permeability, evaluated in the Caco-2 cell system by reducing the calcium concentration in the media to increase the pore size of the tight junctions, most likely contributes only minimally to the oral absorption of the compounds. All six compounds were shown to be efflux substrates displaying concentration-dependent saturation of efflux. The efflux could be blocked by cyclosporine A, a specific P-glycoprotein (P-gp) inhibitor, suggesting that P-gp may be the responsible transporter. Oral absorption in rats was calculated using in vivo oral bioavailability and hepatic extraction ratios. Human oral absorption was projected to be similar to that of rats, as reported previously by comparing rat and human absorption values for 23 marketed drugs. Upon comparison of human oral absorption predicted by Caco-2 permeability and by rat pharmacokinetics, we show a better correlation with Caco-2 permeability obtained at higher compound concentrations, where efflux is saturated, than at lower concentrations. The higher concentrations are likely reflecting the lumen concentrations after in vivo oral dosing. The results presented in this study demonstrate that, when tested at relevant compound concentrations, Caco-2 permeability is useful for predicting the oral absorption of peptidic compounds.

Prediction of oral absorption in humans by experimental immobilized artificial membrane chromatography indices and physicochemical descriptors

The purpose of the present study was to examine the human oral absorption (HOA) predictability of the experimentally determined immobilized artificial membrane (IAM) chromatography capacity factor ( log k ′ IAM ) in conjunction with physicochemical descriptors. Transcellular permeation was modeled based on determination of log k ′ IAM considering pH partition hypothesis, and the independent variables were polar surface area (PSA) and molecular weight (MW). The correlation between log k ′ IAM determined at different pH and n-octanol/water partition coefficient (log P) and contribution of polarity (PSA) and size (MW) in the transcellular permeation model were the extension to the previous work. A data set of 37 compounds with partition coefficient values taken from the literature was employed to show importance of ionic interaction in oral absorption prediction. The highest log k ′ IAM value among screened pH 4.5, 5.5, 6.5 and 7.4 ( log k ′ IAM 4.5 − 7.4 ) in conjunction with PSA predicted HOA with coefficient of determination (CD) of 0.9001 compare to log k ′ IAM 4.5 − 7.4 alone with CD of 0.8454 after excluding bretylium from the set of 28 structurally diverse drugs for known reason. PSA helped to avoid over estimation of HOA for amiloride, famotidine and furosemide. The model was tested for its applicability in drug development program and found to predict oral absorption using physically meaningful and structurally related properties making them relatively straightforward for a medicinal chemist to interpret.

Investigation of Regional Mechanisms Responsible for Poor Oral Absorption in Humans of a Modified Release Preparation of the α-Adrenoreceptor Antagonist, 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003): The Rational Use of ex Vivo Intestine to Predict in Vivo Absorption

Modified release (MR) formulations are used to enhance the safety and compliance of existing drugs by improving their pharmacokinetics. Predicting the likely success of MR formulations is often difficult before clinical studies. A systematic in vitro approach using mouse and human tissues was adopted to rationalize the in vivo pharmacokinetics of 9- and 15-h MR formulations of an alpha-adrenoreceptor antagonist, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4 tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (UK-338,003). Immediate release UK-338,003 was well absorbed in humans consistent with moderate Caco-2 cell monolayer permeability. In contrast, 9- and 15-h modified release formulations showed marked reductions in C(max) (47.1 and 68.9%) and AUC(0-72) (32.6 and 54.0%). Colonic intubation resulted in 81.3 and 73.8% reductions in C(max) and AUC(0-72). Mechanistic studies in isolated mouse tissues showed that colonic UK-338,003 permeability (P(app) < 0.5 x 10(-6) cm/s) was at least 40 times lower than that for ileum with marked asymmetry. UK-338,003 was found to be a substrate for P-glycoprotein (PGP) with a weaker interaction for multidrug resistance-associated protein-type transporters in mouse intestine. PGP inhibition dramatically increased colonic UK-338,003 permeability to the levels observed in ileum. Low UK-338,003 apical to basolateral permeability was also observed in ex vivo human distal intestine, but both the asymmetry and increase in permeability after PGP inhibition were significantly lower. In conclusion, the poor absorption of MR UK-338,003 in humans can be explained by a combination of PGP-dependent efflux and low intrinsic permeability in the lower bowel. Regional permeability studies in ex vivo tissues used during drug development can highlight absorption problems in the distal bowel and assess the feasibility of developing successful MR formulations.

QSAR study on permeability of hydrophobic compounds with artificial membranes

We previously reported a classical quantitative structure–activity relationship (QSAR) equation for permeability coefficients ( P app-pampa) by parallel artificial membrane permeation assay (PAMPA) of structurally diverse compounds with simple physicochemical parameters, hydrophobicity at a particular pH (log P oct and |p K a − pH|), hydrogen-accepting ability ( SA HA), and hydrogen-donating ability ( SA HD); however, desipramine, imipramine, and testosterone, which have high log P oct values, were excluded from the derived QSAR equation because their measured P app-pampa values were lower than calculated. In this study, for further investigation of PAMPA permeability of hydrophobic compounds, we experimentally measured the P app-pampa of more compounds with high hydrophobicity, including several pesticides, and compared the measured P app-pampa values with those calculated from the QSAR equation. As a result, compounds having a calculated log P app-pampa > −4.5 showed lower measured log P app-pampa than calculated because of the barrier of the unstirred water layer and the membrane retention of hydrophobic compounds. The bilinear QSAR model explained the PAMPA permeability of the whole dataset of compounds, whether hydrophilic or hydrophobic, with the same parameters as the equation in the previous study. In addition, PAMPA permeability coefficients correlated well with Caco-2 cell permeability coefficients. Since Caco-2 cell permeability is effective for the evaluation of human oral absorption of compounds, the proposed bilinear model for PAMPA permeability could be useful for not only effective screening for several drug candidates but also the risk assessment of chemicals and agrochemicals absorbed by humans.

Prediction of Human Drug Absorption Using Liposome Electrokinetic Chromatography

With the tremendously increasing numbers of novel drug candidates, there remains a compelling need for rapid screening methods for drug-like physiochemical and pharmacokinetic properties. Different technologies have emerged that enable rapid screening in vitro for sorting out new chemical entity (NCE) classes. It is invaluable for these technologies being developed early in the drug discovery process to avoid the loss of cost and time in late development due to poor absorption and/or bioavailability. In this study, liposome electrokinetic chromatography (LEKC) serves as a convenient, rapid and cost-effective tool to determine lipophilicity and to predict human oral absorption. Twenty-seven organic neutral molecules were evaluated by octanol/water system (log P ow) and LEKC (log k), and linear solvation energy relationship (LSER) analysis was conducted to compare the retention mechanism between LEKC and octanol/water system. LEKC can provide a rapid indirect measurement of log P ow for small organic neutral molecules. A clearly sigmoidal relationship could be seen by correlating log k with the fraction of 25 drugs absorbed in humans (Fa), and the outliers suggested the involvement of non-transcellular passive diffusion, e.g. active transport, paracellular route; on the contrary, it is not the case with the octanol/water system. Therefore, LEKC, in combination with other permeability prediction model, can provide a primary screen for a large number of drug candidates at early stage of the drug discovery process with high-throughput and at low-cost.

Prediction and Mechanistic Interpretation of Human Oral Drug Absorption Using MI-QSAR Analysis

Membrane-interaction [MI]-QSAR analysis, which includes descriptors explicitly derived from simulations of solutes [drugs] interacting with phospholipid membrane models, was used to construct QSAR models for human oral intestinal drug absorption. A data set of 188 compounds, which are mainly drugs, was divided into a parent training set of 164 compounds and a test set of 24 compounds. Stable, but not highly fit [R2 = 0.68] MI-QSAR models could be built for all 188 compounds. However, the relatively large number [47] of drugs having 100% absorption, as well as all zwitterionic compounds [11], had to be eliminated from the training set in order to construct a linear five-term oral absorption diffusion model for 106 compounds which was both stable [R2 = 0.82, Q2 = 0.79] and predictive given the test set compounds were predicted with nearly the same average accuracy as the compounds of the training set. Intermolecular membrane-solute descriptors are essential to building good oral absorption models, and these intermolecular descriptors are displaced in model optimizations and intramolecular solute descriptors found in published oral absorption QSAR models. A general form for all of the oral intestinal absorption MI-QSAR models has three classes of descriptors indicative of three thermodynamic processes: (1) solubility and partitioning, (2) membrane-solute interactions, and (3) flexibility of the solute and/or membrane. The intestinal oral absorption MI-QSAR models were compared to MI-QSAR models previously developed for Caco-2 cell permeation and for blood-brain barrier penetration. The MI-QSAR models for all three of these ADME endpoints share several common descriptors, and suggest a common mechanism of transport across all three barriers. A further analysis of these three types of MI-QSAR models has been done to identify descriptor-term differences across these three models, and the corresponding differences in thermodynamic transport behavior of the three barriers.

Human oral drugs absorption is correlated to their in vitro uptake by brush border membrane vesicles

Brush border membrane vesicles (BBMV) were prepared from the rabbit small intestine for testing drug absorption potency through the enterocyte's apical membrane, which is an important compartment for drug oral absorption. Some modifications have been made to the traditional vesicle assay for adapting it to the 96-well plate format. The accumulation of 23 reference drugs was measured, and the data showed a good correlation with human oral absorption with a correlation coefficient R = 0.853 ( P < 0.001), with the exception of a few false positive results. As the measured drug absorption may contain a membrane/protein binding component as well as drug uptake into vesicles, these two fractions can be discriminated by changing extravesicular osmolarity using different mannitol concentrations. This model can be applied for evaluating drug absorption rate/mechanisms, and helping drug selection in early drug research and development.

Relationship between immobilized artificial membrane chromatographic retention and human oral absorption of structurally diverse drugs

Capacity factors are determined for a set of drugs for which human oral absorption (HOA) data are available, using immobilized artificial membrane (IAM) chromatography. The compound set represented acidic, basic, neutral and amphoteric drugs from various structure classes and having low to high human oral absorption. Effect of mobile phase pH on retention was investigated to determine the optimal condition for better correlation with HOA. The retention (capacity factor, k ′ IAM ) of each drug was measured by reverse phase HPLC using an IAM.PC.DD2 (1 cm × 3 mm i.d., 12 μm) column with an eluent of acetonitrile—0.01 M phosphate buffer at pH 4.5–7.4. The pH dependent k ′ IAM was in accordance with pH partition theory. Using non-linear regression analysis the obtained log k ′ IAM values were compared with published data on HOA in order to establish correlation. The better correlation with HOA was observed when the highest log k ′ IAM value selected among pH 4.5–7.4 ( R 2 = 0.8566) for each drug rather than obtained at more traditional pH 7.4 ( R 2 = 0.7403). Finally, it was confirmed by Cook's D outlier test that there was no influential observation in the model that affect the relationship between IAM capacity factor and HOA. The assay conditions were optimized and validated to make it suitable for routine analysis and for compound characterization in early discovery where permeability may be an issue.

2,5-Diketopiperazines as Potent, Selective, and Orally Bioavailable Oxytocin Antagonists. 3. Synthesis, Pharmacokinetics, and in Vivo Potency

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.

Development of an in Vitro Rat Intestine Segmental Perfusion Model to Investigate Permeability and Predict Oral Fraction Absorbed

The aims of the study are to develop and evaluate an in vitro rat intestine segmental perfusion model for the prediction of the oral fraction absorbed of compounds and to assess the ability of the model to study intestinal metabolism. The system consisted of a perfusion cell with a rat intestinal segment and three perfusion circulations (donor, receiver, and rinsing circulation). Lucifer yellow (LY) was applied as internal standard together with test compounds in the donor circulation. To validate the model, the permeability of eight noncongeneric passively absorbed drugs was determined. Intestinal N-demethylation of verapamil into norverapamil was followed in the donor and receiver circulations by high-performance liquid chromatography analysis. The in vitro model allowed ranking of the tested compounds according to their in vivo absorption potential. The Spearman's correlation coefficient between the oral fraction absorbed in humans and the ratio of permeation coefficient of test compound to the permeation coefficient of LY within the same experiment was 0.98 (P < 0.01). Moreover, intestinal N-demethylation of verapamil, its permeation, and the permeation of its metabolite norverapamil could be assessed in parallel. Up to six permeation kinetics can be obtained per rat, and the method has shown to be a valuable tool to estimate human oral absorption.

Oral Absorption of Poorly Water-Soluble Drugs: Computer Simulation of Fraction Absorbed in Humans from a Miniscale Dissolution Test

The purpose of this study was to develop a new system for computer simulation to predict fraction absorbed (F(a)) of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs after oral administration to humans, from a miniscale dissolution test. Human oral absorption of 12 lipophilic drugs was simulated theoretically by using the dissolution and permeation parameters of the drugs. A miniscale dissolution test and a solubility study were carried out in a conventional buffer and a biorelevant medium (pH 6.5). A dissolution parameter, which can simulate in vivo dissolution, was obtained from the in vitro dissolution curve. Human intestinal permeability was estimated assuming that the permeation was limited by diffusion through the unstirred water layer. The F(a) in humans was predicted and then compared with clinical data. The dissolution and solubility of most model drugs were faster and higher in a biorelevant medium than in a conventional buffer. The simulated absorption was limited by the drug dissolution rate and/or solubility. Predicted F(a) was significantly correlated with clinical data (correlation coefficient r2 = 0.82, p < 0.001) when the dissolution profiles in biorelevant medium were used for the simulation. This new system quantitatively simulated human absorption and would be beneficial for the prediction of human F(a) values for BCS class II drugs.