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The gastrointestinal uptake of macrocyclic compounds is not fully understood. Here we applied our previously validated integrated system based on machine learning and conformal prediction to predict the passive fraction absorbed (f

The blood-brain barrier is often perceived as relatively impermeable, and various cut-off values for zero or limited brain permeability have been suggested. The validity of these values has been evaluated in this review. The barrier appears to have a very high permeability and absorptive capacity: sufficient to absorb compounds with polar surface area270 A(2), molecular weight1,000 Da, log D-3.5 and equilibrium brain-to-blood concentration ratio0.01 well. Sufficient intestinal uptake indicates good passive brain uptake potential. The uptake is potentially more sensitive to involvement and changes of active transport than in the intestines. A physiologically based in vitro-in vivo method for prediction of brain uptake is presented.

Permeability (Pe) and solubility/dissolution are two major determinants of gastrointestinal (GI) drug absorption. Good prediction of these is crucial for predicting doses, exposures and potential interactions, and for selecting appropriate candidate drugs. The main objective was to evaluate screening methods for prediction of GI Pe, solubility/dissolution and fraction absorbed (fa) in humans. The most accurate Pe models for prediction of fa of passively transported and highly soluble compounds appear to be the 2/4/A1 rat small intestinal cell model (in-vitro and in-silico), a newly developed artificial-membrane method, and a semi-empirical approach based on in-vitro membrane affinity to immobilized lipid bilayers, effective molecular weight and physiological GI variables. The predictability of in-vitro Caco-2, in-situ perfusion and other artificial membrane methods seems comparably low. The Pe and fa in humans for compounds that undergo mainly active transport were predicted poorly by all models investigated. However, the rat in-situ perfusion model appears useful for prediction of active uptake potential (complete active uptake is generally well predicted), and Caco-2 cells are useful for studying bidirectional active transport, respectively. Human intestinal in-vitro Pe, which correlates well with fa for passively transported compounds, could possibly also have potential to improve/enable predictions of fa for actively transported substances. Molecular descriptor data could give an indication of the passive absorption potential. The ‘maximum absorbable dose’ and ‘dose number’ approaches, and solubility/dissolution data obtained in aqueous media, appear to underestimate in-vivo dissolution to a considerable extent. Predictions of in-vivo dissolution should preferably be done from in-vitro dissolution data obtained using either real or validated simulated GI fluids.

The mechanisms controlling rates and routes for intestinal absorption of nutrients and small compounds are still not fully clarified. In the present study we aimed to investigate the effect of solvent drag on intestinal permeability of compounds with different molecular sizes in humans and rats. The effective intestinal permeabilities (P eff ) of hydrophilic compounds (MW 60-4000) were determined in the single-pass perfused jejunum in humans in vivo and rats in situ under iso- and hypotonic conditions. The transport mechanism(s) of water and the importance of the solvent drag effect were investigated by the use of D 2 O. This is the first report in humans establishing the relation between in vivo measured jejunal P eff and molecular size for hydrophilic compounds. In addition, in rats we also found a molecular-size selectivity for hydrophilic compounds similar to man. The jejunal P eff of water and urea (MW 60) in both species were several times higher than predicted from their physicochemical properties. In humans, the jejunal absorption of urea and creatinine (MW 113) was increased by solvent drag, while no effect was found for the other investigated compounds. In rats, P eff for urea and creatinine were unaffected. In conclusion, it is still unclear if solvent drag occurs mainly through the para- or transcellular route, although, results from this study further add to our earlier reports suggesting that the transcellular route is most important from a quantitative point of view regardless of physicochemical properties of the transported compounds.

The goal of this study was to determine the most appropriate hydrodynamic model for the Loc-I-Gut in-vivo perfusion system. The general mixing-tank-in-series model, which can approximate single mixing tank and laminar and plug-flow hydrodynamics, was fitted to the observed experimental residence-time distribution curves for the non-absorbable marker [14C]PEG 4000. The residence-time distribution analysis shows that the hydrodynamics of the perfusion solution within the jejunal segment in man is well approximated by a model containing on average between 1–2 mixing tanks in series. The solution is well mixed when using perfusion rates of 20, 30 and 60 mL min−. The average mean residence time estimates from the fitted residence-time distribution were 12 ± 7.6, 15 ± 4.2 and 7.7 ± 4.6 min, respectively, at these three perfusion rates. The mean volumes of the segment (Vs) were 25 ± 15, 45 ± 12 and 46 ± 27 mL, respectively. There were no statistical differences between 20, 30 and 60 mL min− in respect of the number of mixing tanks (n) and mean residence times. This residence-time distribution analysis indicates that the luminal fluid in the Loc-I-Gut perfusion system is well-mixed, and that permeability calculations based on the well-mixed assumption most closely approximate the actual local (average) membrane permeability within the perfused segment.

Physiologically based methods generally perform poorly in predicting in-vivo hepatic CL (CLH) from intrinsic clearance (CLint) in microsomes in-vitro and unbound fraction in blood (fu,bl). Various strategies to improve the predictability have been developed, and inclusion of an empirical scaling factor (SF) seems to give the best results. This investigation was undertaken to evaluate this methodology and to find ways to improve it further. The work was based on a diverse data set taken from Ito and Houston (2005). Another objective was to evaluate whether rationalization of CLH predictions can be made by replacing blood/plasma-concentration ratio (Cbl/Cpl) measurements with SFs. There were apparently no or weak correlations between prediction errors and lipophilicity, permeability (compounds with low permeability missing in the data set) and main metabolizing CYP450s. The use of CLint class (high/low) and drug class (acid/base/neutral) SFs (the CD-SF method) gives improved and reasonable predictions: 1.3-fold median error (an accurate prediction has a 1-fold error), 76% within 2-fold-error, and a median absolute rank ordering error of 2 for CLH (n = 29). This approach is better than the method with a single SF. Mean (P < 0.05) and median errors, fraction within certain error ranges, higher percentage with most accurate predictions, and ranking were all better, and 76% of predictions were more accurate with this new method. Results are particularly good for bases, which generally have higher CLH and the potential to be incorrectly selected/rejected as candidate drugs. Reasonable predictions of fu,bl can be made from plasma fu (fu,pl) and empirical blood cell binding SFs (B-SFs; 1 for low fu,pl acids; 0.62 for other substances). Mean and median fu,bl prediction errors are negligible. The use of the CD-SF method with predicted fu,bl (the BCD-SF method) also gives improved and reasonable results (1.4-fold median error; 66% within 2-fold-error; median absolute rank ordering error = 1). This new empirical approach seems sufficiently good for use during the early screening; it gives reasonable estimates of CLH and good ranking, which allows replacement of Cbl/Cpl measurements by a simple equation.

This review has evaluated the Biopharmaceutics Classification System (BCS) and improvements have been proposed. The BCS has a very strict solubility/dissolution limit, a generous Pe-limit (≥ 14-times higher rate constant limit for dissolution than for permeation), and is stricter for drugs with a long half-life (t1/2). Available human in-vivo, in-vitro, and in-silico Pe-methods cannot classify Pe for moderately to highly permeable substances sufficiently well, and in-vitro data often underpredict the in-vivo dissolution potential and rate. Good in-vivo dissolution and absorption can be expected for most high Pe drug products. It has not been possible to find a highly permeable product with a Dose number (Do) < 385 (< 2400 in the fed state) that is clearly incompletely absorbed, and near complete uptake has been shown for a drug product with a Do of 660000. The potential implication of these findings is that many true BCS Class I drug products are incorrectly classified. This could be a reason for the limited use of this system. On this basis, it has been suggested that: the limit for high for solubility/dissolution is decreased (to >40 and >95% dissolved within 30min and 3 h, respectively); the limit for high Pe is increased (to >Pe of metoprolol); accurate Pe-models or in-vivo fraction absorbed data are used; solubility/dissolution tests are performed using real or validated simulated gastrointestinal fluids; in-vitro/in-vivo dissolution relationships are established; the t½ is considered; and the rate-limiting step for in-vivo absorption is determined. A major change could be to reduce the BCS into two classes: permeation-rate (Class I) or dissolution-rate (Class II) limited absorption. It is believed that this could give a better balance and increase the number of biowaivers.

The objective was to establish in vitro passive permeability (P e) vs in vivo fraction absorbed (f a)-relationships for each passage through the human intestine, liver, renal tubuli and brain, and develop a P e-based ADME/PK classification system (PCS). P e- and intestinal f a-data were taken from an available data set. Hepatic f a was calculated based on extraction ratios of the unbound fraction of drugs (with support from animal in vivo uptake data). Renal f a (reabsorption) was estimated using renal pharmacokinetic data, and brain f a was predicted using animal in vitro and in vivo brain P e-data. Hepatic and intestinal f a-data were used to predict bile excretion potential. Relationships were established, including predicted curves for bile excretion potential and minimum oral bioavailability, and a 4-Class PCS was developed: I (very high P e; elimination mainly by metabolism); II (high P e) and III (intermediate P e and incomplete f a); IV (low P e and f a). The system enables assessment of potential drug–drug transport interactions, and drug and metabolite organ trapping. The PCS and high quality P e-data (with and without active transport) are believed to be useful for predictions and understanding of ADME/PK, elimination routes, and potential interactions and organ trapping/toxicity in humans.

Because the absorption of orally administered drugs depends on intestinal permeability, we have investigated how absorptive capacity varies from the proximal to distal intestine in rats. The effective permeabilities of compounds with a range of physicochemical properties and different absorption mechanisms were estimated by use of a previously validated in-situ, single-pass perfusion model. The low colonic permeabilities of d-glucose and l-dopa indicate the absence or low capacity of the glucose-and amino-acid-transporters in this region. With the exception of the small and moderately lipophilic nonsteroidal anti-inflammatory drug, naproxen, for which permeability was maintained throughout the intestine, the passive intestinal permeabilities for hydrophilic and lipophilic drugs were approximately twice as high in the jejunum and ileum as in the colon. These observations are in accord with those made in recent studies. However, the reasons for the high colonic permeability of non-steroidal anti-inflammatory drugs, and results obtained in previous animal experiments demonstrating that the colon is the region of the intestine with the highest absorptive capacity were not fully clarified. These data show that the permeability to hydrophilic and lipophilic drugs decreases along the intestine, whereas it is maintained throughout the intestine for the small and moderately lipophilic naproxen. Further investigations are required to clarify the interplay between membrane composition, fluidity and permeability under various conditions in different absorption models.

The absorption mechanism(s) of terbutaline in the human jejunum was studied by using the intestinal perfusion instrument, Loc-I-Gut. The present study was divided into three parts. In Part I the absorption of 10 and 20 microM of both (+) and (-)-terbutaline enantiomers was studied. The influence of D-glucose (80 mM) on the net fluid transport across the intestinal wall and the effective intestinal permeability (Peff) of both (+/-)-terbutaline (10 microM) and antipyrine (0.5 mM) was investigated in Part II. The experimental design of Part III was similar to that in Part II, with the exception that the perfusion solution was hypotonic and had a D-glucose concentration of 80 mM. No statistical differences were found in the Peff between terbutaline enantiomers or their concentrations. D-glucose (80 mM) did neither affect net fluid transport nor the Peff of (+/-)-terbutaline and antipyrine in the human jejunum. In contrast, hypotonic D-glucose (80 mM) solution induced a net fluid absorption (p0.01). In parallel with this observation, the Peff -value of (+/-)-terbutaline was unchanged, whereas the absorption of antipyrine was found to be significantly increased (p0.05). The increased permeability of antipyrine during the net fluid absorption phase might be due to convective paracellular flow, but more likely is it a consequence of a higher concentration gradient of the drug close to the intestinal wall, and thereby increased transcellular absorption. Based on these findings we propose that the major route for the oral absorption of terbutaline and antipyrine might be passive transcellular diffusion.