SPR biosensor studies of the direct interaction between 27 drugs and a liposome surface: correlation with fraction absorbed in humans.
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Humans↗
Biomedical subjects
H Lennernäs
Publications and source records attributed to H Lennernäs.
Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter.
One approach to increase drug stability and to facilitate oral absorption of low bioavailability drugs may be to design oligopeptide ester prodrugs which are stable in the gastrointestinal tract, are transported via the oligopeptide transporter, and finally release the parent drug molecule into the blood circulation and/or by its site of action. In these kinds of prodrugs the ester linkage may be broken by pH dependent and/or enzyme catalyzed hydrolysis. The objective of the present study was to investigate the degradation mechanism and rate of the model compounds Glu(OBzl)-Sar, D-Glu(OBzl)-Ala and Asp(OBzl)-Sar in aqueous solution and in relevant biological media and to compare these results with those of our previous study of D-Asp(OBzl)-Ala. Furthermore, the resulting aqueous stability and in vitro metabolism data are related to our previous affinity data to evaluate if Glu-Sar, D-Glu-Ala, and Asp-Sar have potential as pro-moieties in these kinds of prodrugs. The degradation rates follow first-order kinetics, show maximun stability at pH 4-5 with maximum half-lives for Asp(OBzl)-Sar, Glu(OBzl)-Sar, and D-Glu(OBzl)-Ala of 115 h, 30 days and 152 days, respectively. The stability was dependent on buffer concentration, temperature, pH, and ionic strength. In biological media such as 80% human plasma, human gastric juice and intestinal fluid, and 10% rat jejunal homogenate at 37 degrees C, the half-lives were greater than 1 h except for the hydrolysis of Glu(OBzl)-Sar in 10% rat jejunal homogenate, where the half-life was approximately 16 min. All the stabilized dipeptides may have potential as drug carriers targeting hPepT1.
Animals↗
Dissolution of hydrocortisone in human and simulated intestinal fluids.
PURPOSE: To compare solubility and dissolution rate of hydrocortisone in aspirated human intestinal fluids (HIFs) with simulated intestinal fluids (SIFs) and buffer. METHODS: Solubility and flux from a rotating disk of hydrocortisone were measured. The bile salt content, pH and osmotic pressure were determined in HIFs. RESULTS: In fasted state the solubility of hydrocortisone was higher in HIFs than in the buffer and SIFs. The flux of hydrocortisone in HIFs was similar to the flux in the buffer but lower than the flux in SIFs at fasted state. Addition of intestinal surfactants in SIFs increased solubility and flux at both fasted and fed state. The increase in solubility was caused by micelle formation in SIFs. The increase in flux may partly be explained by increased solubility. The bile salt content of the HIFs did not correlate with the solubility or the flux but pH in the HIFs seems to have some effect on the components of the HIFs resulting in increased solubility. CONCLUSIONS: It is possible to perform comparable dissolution tests in HIFs and SIFs. The lack of correlation between the results in HIFs and the bile salt content may be explained by the relatively low lipophilicity of the model drug.
Anti-Inflammatory Agents↗
Investigations of the in-vitro metabolism of three opioid tetrapeptides by pancreatic and intestinal enzymes.
The metabolism of three opioid tetrapeptides, Tyr-D-Arg-Phe-Nva-NH2, Tyr-D-Arg-Phe-Phe-NH2 and Tyr-D-Ala-Phe-Phe-NH2, was investigated in the presence of pure pancreatic enzymes (trypsin, chymotrypsin, elastase, carboxypeptidase A and carboxypeptidase B), as well as in the presence of pure carboxylesterase and aminopeptidase N. The cleavage patterns of the pure pancreatic enzymes were then compared with those found in rat and human jejunal fluid. Metabolism was also studied in homogenates from different intestinal regions (duodenum, jejunum, ileum and colon) and in enterocyte cytosol from rats. The effect of various protease inhibitors was investigated in the jejunal homogenate. The parent peptides were assayed by high-performance liquid chromatography and metabolites were identified by means of liquid chromatography-mass spectrometry. Of the pure enzymes, the quickest hydrolysis of the peptides was observed for the pancreatic enzymes chymotrypsin, trypsin and carboxypeptidase A. In most cases they formed the corresponding deamidated tetrapeptides (chymotrypsin and trypsin) or tripeptides with a missing C-terminal amino acid (carboxypeptidase A). Regional differences in intestinal metabolism rates were found for all three peptides (P < 0.001), with the highest rates observed in jejunal and/or colonic homogenates. The deamidated tetrapeptides were formed both in rat intestinal homogenates and in enterocyte cytosol. Metabolism in the jejunal homogenate was markedly inhibited by some serine and combined serine and cysteine protease inhibitors. In conclusion, the C-terminal amide of these tetrapeptides did not fully stabilise them against intestinal deamidase and carboxypeptidase activities. The significant hydrolysis of the peptides by pure chymotrypsin, trypsin and carboxypeptidase A showed that lumenal pancreatic proteases might be a clear metabolic obstacle in oral delivery even for small peptides such as these tetrapeptides.
Animals↗
Enantiometric separation of verapamil and norverapamil using Chiral-AGP as the stationary phase.
Simultaneous enantiomeric separation of verapamil and its main metabolite norverapamil was achieved using Chiral-AGP as the stationary phase. The optimized chromatographic system was obtained using statistical experimental design with partial least squares as regression method. The three variables studied were buffer pH, content of acetonitrile and column temperature. A high buffer pH favors enantioselectivity as well as the selectivity between (S)-verapamil and (R)-norverapamil. The concentration of the organic modifier in the mobile phase was a compromise as a high content of acetonitrile decreased enantioselectivity but increased the selectivity mentioned above. Increased column temperature increased the separation between (S)-verapamil and (R)-norverapamil with only a slight decrease in enantioresolution.
Calcium Channel Blockers↗
Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography.
Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.
Animals↗
A comparison between direct determination of in vivo dissolution and the deconvolution technique in humans.
AIM: The primary objective of this study was to investigate the in vivo dissolution of carbamazepine in humans and to compare it with the dissolution estimated by deconvolution of plasma concentrations as well as the in vitro dissolution. METHODS: The in vivo study included six healthy volunteers, and consisted of two sequential parts. In part 1 the dissolution was measured by perfusing a semi-open segment in the proximal jejunum in humans. In part 2 the volunteers were given a solution of carbamazepine orally. In both parts of the study, plasma samples were collected up to 48 h after administration of the dose. The in vitro dissolution was measured in a flow-through cell using dissolution medium with and without the addition of bile acids (3 mM). RESULTS: The direct measured in vivo dissolution profile of carbamazepine and the deconvoluted profile were found to be similar. The two dissolution profiles of carbamazepine obtained in vitro were statistically lower than the two in vivo dissolution profiles. The higher in vivo dissolution rate is probably due to efficient sink conditions as a consequence of the high permeability of carbamazepine and more pronounced intestinal motility. CONCLUSION: The jejunal perfusion system was successfully used for in vivo dissolution measurements of carbamazepine and agreed with the deconvoluted plasma profile regarding rate and extent of dissolution. Single-pass perfusion is therefore a meaningful tool for further studies of in vivo dissolution.
Algorithms↗
Stability, metabolism and transport of D-Asp(OBzl)-Ala--a model prodrug with affinity for the oligopeptide transporter.
The model prodrug D-Asp(OBzl)-Ala has previously been shown to have affinity and to be transported by the oligopeptide transporter PepT1 expressed in Caco-2 cells. The main objective of the present study was to investigate the aqueous stability of D-Asp(OBzl)-Ala and its in vitro metabolism in different gastrointestinal media arising from rats and humans, as well as in human plasma. The second major aim of the study was to evaluate our previous study in Caco-2 cell culture, by determining the effective intestinal permeability (Peff) of D-Asp(OBzl)-Ala in situ using the single-pass rat perfusion model. The aqueous stability studies show water, general buffer, as well as specific acid and base catalysis of D-Asp(OBzl)-Ala. The degradation of the model prodrug was independent of ionic strength. The half-lives in rat jejunal fluid and homogenate were >3 h. In human gastric and intestinal fluids, the half-lives were >3 h and 2.3+/-0. 03 h, respectively. Using the rat single-pass perfusion technique, the effective jejunal permeability (Peff) of D-Asp(OBzl)-Ala was determined to be high (1.29+/-0.5.10-4 cm/s). The 32 times higher Peff value found in the perfusion model compared to Caco-2 cells is most likely due to a higher functional expression of the oligopeptide transporter. Rat jejuna Peff was reduced by approximately 50% in the presence of well known oligopeptide transporter substrates, such as Gly-Sar and cephalexin. It may be that D-Asp(OBzl)-Ala is primarily absorbed intact by the rat jejunal oligopeptide transporter, since the stability in the intestinal homogenate and fluids was rather high (t1/2>2.3 h).
Algorithms↗
Chitosans as absorption enhancers of poorly absorbable drugs. 3: Influence of mucus on absorption enhancement.
Chitosans are potent nontoxic absorption enhancers after nasal administration but their effects on the intestinal epithelium in vivo has not been studied in detail. In this study, the effects of chitosans with varying molecular weights and degrees of acetylation on the absorption of a poorly absorbed model drug (atenolol) were studied in intestinal epithelial cell layers with or without a mucus layer and in an in situ perfusion model of rat ileum. The effects of the chitosans on epithelial morphology and release of lactate dehydrogenase (LDH) into the perfusate were investigated in the in situ model. The chitosans had pronounced effects on the permeability of mucus-free Caco-2 layers and enhanced the permeation of atenolol 10- to 15-fold, with different absorption kinetics for different chitosans, in accordance with previous results. In contrast, enhancement of atenolol absorption through rat ileum was modest. LDH release from the tissues perfused with chitosans did not increase, indicating that the chitosans were used at nontoxic concentrations. Morphological examination of the perfused ileal tissues revealed more mucus discharge from the tissues exposed to chitosans than from controls, which suggested that the discharged mucus may inhibit the binding of chitosan to the epithelial surface and hence decrease the absorption-enhancing effect. This hypothesis was supported by studies with intestinal epithelial HT29-H goblet cells covered with a mucus layer. The binding of chitosan to the epithelial cell surface and subsequent absorption-enhancing effects were significantly reduced in mucus-covered HT29-H cultures. When the mucus layer was removed prior to the addition of chitosan, the cell surface binding and absorption-enhancing effects of the chitosans were increased. We conclude that the modest absorption-enhancing effects of unformulated chitosan solutions in the perfused rat ileum are a result of the mucus barrier in this tissue. This effect may be overcome by increasing the local concentrations of both chitosan and drug, i.e,. through formulation of the chitosan into a particulate dosage form.
Adrenergic beta-Antagonists↗
Stability and perfusion studies of Desmopressin (dDAVP) and prodrugs in the rat jejunum.
Three aliphatic carboxylic acid esters of the tyrosine phenolic group in Desmopressin (dDAVP) were investigated in vitro for their stability and metabolism in rat gastrointestinal media. The degradation followed strictly first-order kinetics and the prodrugs were quantitatively converted to dDAVP. The n-hexanoyl (II) and n-octanoyl (III) esters were rapidly hydrolysed in 10% rat jejunal fluid showing half-lives of 1.1+/-0.2 min and 1.4+/-0.1 min, respectively. In 5 % rat jejunal homogenate the half-lives were 3.2+/-0.2 min and <30 sec, respectively. The sterically hindered pivalate ester (I) proved to be more stable. The half-lives were 10.3+/-0.3 min in 10% rat jejunal fluid and 1.5+/-0.1 min in 10% rat jejunal homogenate, respectively. The presence of paraoxon, an inhibitor of type B esterases significantly decreased the degradation rate of the pivalate ester (I) in rat jejunal fluid (t1/2 > 5 hrs) indicating that the prodrug is converted to dDAVP by rapid luminal breakdown of the ester bond. It was shown that approximately 13 % of prodrug I disappeared from the gut lumen during a single-pass perfusion experiment in rat jejunum. Our results indicate that the disappearance from the jejunal lumen was primarily caused by degradation of the prodrug to dDAVP by esterases rather than absorption. The better stability of the sterically hindered prodrug (I) indicate that even more sterically hindered prodrugs will be a better choice for a further optimization of stability and lipophilicity, and consequently a potentially improved intestinal absorption of dDAVP.
Animals↗
Surface activity and concentration dependent intestinal permeability in the rat.
PURPOSE: To investigate the relation between intestinal effective permeability (P(eff)) and surface activity of fluvastatin and verapamil. METHODS: P(eff)-values were determined for fluvastatin, antipyrine and D-glucose following colon perfusions in the rat in situ. The perfusion solitions differed regarding concentrations of fluvastatin (0-2500 microM) and surface tension (58.9-43.7 mN/m). A cellulose derivative, ethyl-(hydroxyethyl) cellulose (EHEC), was added to lower the surface tension of one of the perfusion solutions. The surface tension of perfusion solutions containing R/S-verapamil (8-814 microM) and R/S-verapamil + chlorpromazine (814 microM + 10 mM) were related to the corresponding P(eff)-values from the literature. RESULTS: The P(eff)of fluvastatin correlated inversely (r2 = 0.985, p < 0.05) with the surface tension of the perfusion solutions below the critical micelle concentration (CMC, 1 mM). Decreasing the surface tension with EHEC increased the P(eff) of fluvastatin by 36% (p < 0.001), but not to the extent anticipated from the correlation between the P(eff) and the surface tension. EHEC also increased the P(eff) of antipyrine by 49% (p < 0.01 ) but not for D-glucose. The P(eff) of R/S-verapamil correlated inversely with the surface tension (r2 = 0.980, p < 0.001). CONCLUSIONS: The ability of fluvastatin to decrease the surface tension at the membrane surface can partly explain the concentration dependent colonic P(eff) of fluvastatin. This study shows that the surface activity of the drug molecule itself is an important physicochemical factor that should be taken into consideration when evaluating drug absorption studies performed in vitro or in situ.
Animals↗
Jejunal permeability in humans in vivo and rats in situ: investigation of molecular size selectivity and solvent drag.
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 (Peff) 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 D2O. This is the first report in humans establishing the relation between in vivo measured jejunal Peff 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 Peff 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, Peff 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.
Animals↗
The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans.
AIMS: The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first-pass metabolism of (R)- and (S)-verapamil in humans. METHODS: A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)-verapamil was 120 mg l-1 in both periods, and ketoconazole was added at 40 mg l-1 in period 2. (R/S)-verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)- and (S)-norverapamil were also estimated in the outlet jejunal perfusate. RESULTS: The effective jejunal permeability (Peff) of both (R)- and (S)-verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P-glycoprotein mediated efflux. However, the appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)- and (S)-verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)-verapamil by ketoconazole. CONCLUSIONS: Ketoconazole did not affect the jejunal Peff of (R/S)-verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P-glycoprotein than of CYP3A4 in vivo in humans.
Adult↗
Repeated oral rifampicin decreases the jejunal permeability of R/S-verapamil in rats.
The main purpose of this rat study was to investigate the effect of rifampicin on the effective permeability (P(eff)) of R/S-verapamil in the rat jejunum. In addition the effect on metabolism of R/S-verapamil to R/S-norverapamil was examined. In situ single-pass perfusions of the rat jejunum were performed in animals pretreated with oral rifampicin (250 mg/kg/day) or saline (control) over various time periods (1, 4, 7, and 14 days). The jejunal P(eff) of each of the enantiomers of verapamil and D-glucose was estimated. The appearance ratios of the CYP3A-formed metabolites R- and S-norverapamil were also estimated in the outlet jejunal perfusate. The jejunal P(eff) of both R- and S-verapamil decreased as an effect of the oral pretreatment with rifampicin. The appearance of R- and S-norverapamil in the jejunum was also affected by the oral pretreatment with rifampicin, with increasing concentrations of R/S-norverapamil being evident after 14 days of rifampicin pretreatment. There was no stereoselectivity in either the P(eff) of R- and S-verapamil or the metabolic appearance of R- and S-norverapamil. Treatment with oral rifampicin decreased the P(eff) of R/S-verapamil, which is in accordance with an induction of P-glycoprotein activity in the apical enterocyte membrane. The increase in appearance of R/S-norverapamil in jejunum is in accordance with an induction of CYP3A metabolism in the rat.
Algorithms↗
High in situ rat intestinal permeability of artemisinin unaffected by multiple dosing and with no evidence of P-glycoprotein involvement.
The objective of this study was to investigate whether the decrease in artemisinin bioavailability after repeated oral dosing in humans can be a result of increased efflux of artemisinin by P-glycoprotein or decreased membrane transport at the intestinal barrier. The effective jejunal permeability (Peff) of artemisinin was investigated using an in situ rat perfusion model. Fifty-four rats were randomized to one of three treatment arms: no pretreatment, pretreatment with artemisinin emulsion for 5 days (60 mg/kg/day, p.o. ), or pretreatment with emulsion vehicle for 5 days. The rats within each treatment arm were randomized further to be jejunally perfused with either low (500 ng/ml) or high (5000 ng/ml) artemisinin concentration or low artemisinin concentration plus the P-glycoprotein inhibitor R,S-verapamil (400 microg/ml). Perfusate samples were assayed for content of artemisinin, R,S-verapamil, and perfusion viability markers. Artemisinin Peff was 1.44 +/- 0.38, 1. 17 +/- 0.32, and 1.71 +/- 0.29 (.10(-4), cm/s) in rats receiving no pretreatment and perfused with low, high, or low artemisinin concentration plus verapamil, respectively. Multiple oral dosing of artemisinin did not affect the jejunal permeability of artemisinin. R,S-verapamil Peff was similar in artemisinin-pretreated rats (1.09 +/- 0.54. 10(-4), cm/s) and rats pretreated with only vehicle (1.07 +/- 0.37. 10(-4), cm/s). The decrease in artemisinin bioavailability after multiple oral dosing in human is probably not a result of changes in P-glycoprotein expression or general intestinal transport. It seems more likely attributed to increased hepatocellular activity. Furthermore, artemisinin exhibits high jejunal permeability and is neither a substrate nor inducer of P-glycoprotein.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach.
The effective permeability (Peff) in the human jejunum (in vivo) of 22 structurally diverse compounds was correlated with both experimentally determined lipophilicity values and calculated molecular descriptors. The permeability data were previously obtained by using a regional in vivo perfusion system in the proximal jejunum in humans as part of constructing a biopharmaceutical classification system for oral immediate-release products. pKa, log P, and, where relevant, log Pion values were determined using the pH-metric technique. On the basis of these experiments, log D values were calculated at pH 5.5, 6.5, and 7.4. Multivariate data analysis was used to derive models that correlate passive intestinal permeability to physicochemical descriptors. The best model obtained, based on 13 passively transcellularly absorbed compounds, used the variables HBD (number of hydrogen bond donors), PSA (polar surface area), and either log D5.5 or log D6.5 (octanol/water distribution coefficient at pH 5.5 and 6.5, respectively). Statistically good models for prediciting human in vivo Peff values were also obtained by using only HBD and PSA or HBD, PSA, and CLOGP. These models can be used to predict passive intestinal membrane diffusion in humans for compounds that fit within the defined property space. We used one of the models obtained above to predict the log Peff values for an external validation set consisting of 34 compounds. A good correlation with the absorption data of these compounds was found.
Humans↗
Membrane transport of drugs in different regions of the intestinal tract of the rat.
Regional permeability coefficients of 19 drugs with different physicochemical properties were determined using excised segments from three regions of rat intestine: jejunum, ileum, and colon. The results are discussed in relation to the characteristics of the drug, i.e., MW (range 113-1071 Da), pKa, log D (octanol/water at pH 7.4) (range -3.1 to +2.4), and the regional change in the properties of the epithelial membrane. There was a significant decrease in permeability to hydrophilic drugs and a significant increase in permeability for hydrophobic drugs aborally to the small intestine (P < 0.0001). A good correlation could be obtained between MW and permeability coefficients of hydrophilic drugs. The correlation established between the apparent permeability coefficients and the partition coefficients of the drugs was sigmoidal in shape in all three regions and a log D between 0 and 2.5 predicts high permeability values. These permeability data are unique since they result from a diversity of chemical structures with different physicochemical characteristics and a variety of transport mechanisms and they are not influenced by interlaboratory differences. The large regional permeability database in the present study shows the utility of the Ussing chamber technique as a valuable predictive tool for human in vivo data. In addition, the regional permeability profiles obtained suggest a coupling between drug structure and the functional changes of the membrane, which might be useful for selecting a compound for an extended release formulation.
Animals↗
Human intestinal permeability.
This review focuses on permeability measurements in humans, briefly discussing different perfusion techniques, the relevance of human Peff values, and various aspects of in vivo transport mechanisms. In addition, human Peff values are compared with corresponding data from three preclinical transport models. The regional human jejunal perfusion technique has been validated in several important ways. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. Estimations of the absorption half-lives from the measured Peff agree very well with the time to maximal amount of the dose absorbed achieved after an oral dose in humans. We have also shown that it is possible to determine the Peff for carrier-mediated transported compounds and to classify them according to the proposed biopharmaceutical classification system (BCS). Furthermore, human in vivo permeabilities can be predicted using preclinical permeability models, such as in situ perfusion of rat jejunum, the Caco-2 model, and excised intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. Finally, the data obtained in vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It will also be important to study the effect of antitransport mechanisms (multidrug resistance, MDR), such as efflux by P-glycoprotein(s) and gut wall metabolism, for example CYP 3A4, on bioavailability.
Animals↗