495
14 Quantitative Structure-Property Relationship Analysis …
Grass Model describes fluid movement (emptying and transit) in the GI tract
and calculates the drug absorption in each compartment (stomach, duodenum, jejunum, ileum, and colon) over time based primarily on three parameters-solubility,
permeability, and tissue surface area. This model was shown to predict plasma concentration time profiles including the AUC, C max , and t max for ketorolac (BCS 1)
and gancyclovir (BCS 3) well. The software IDEA™ was developed based upon
compartmental models (IDEA™ is not currently available). By using IDEA™, the
fractions of dose absorbed for atenolol (BCS 3), naproxen (BCS 2), and gancyclovir
(BCS 2) in animals and humans were successfully predicted [86]. Similar to GastroPlus™, factors including dose, solubility, and permeability are considered. However, IDEA™ does not take first pass metabolism and drug transport into account.
14.5 Conclusions
Sufficient intestinal absorption of orally administered drugs from the gastrointestinal tract is one of the prerequisites for successful oral drug therapy. It is generally
accepted that the main barrier interrupting drug absorption is formed by the intestinal epithelium and several routes can be followed to pass it. Passive transport often
occurs through the cell membrane of the enterocytes (transcellular transport), this
is the predominant transport route for hydrophobic drugs. Another passive route is
transport via the tight junctions between the enterocytes, i.e., paracellular transport.
Hydrophilic compounds are mostly transported via the paracellular route. Finally,
carrier-mediated transport (influx or efflux) can be observed. Intestinal drug absorption is controlled by dissolution rate and solubility, determining how fast a drug
reaches maximum concentration in the lumenal intestinal fluid, and permeability
coefficient, which relates to the rate at which dissolved drug will cross the intestinal
wall to reach the portal blood circulation. Determination of the dissolution, solubility (at different pH values), and permeability properties of drug candidates can thus
provide information about their absorption potential, and thus allows evaluation of
the compounds according to BCS. The aim of the BCS is to provide a regulatory
tool for replacing certain bioequivalence studies by accurate in vitro dissolution
tests. This will certainly reduce costs and time in the drug development process,
both directly and indirectly, and reduce unnecessary drug exposure in healthy subjects, which is normally the study population in bioequivalence studies. The BCS is
today only intended for oral immediate-release products that are absorbed throughout the intestinal tract. It has been reported that an application of a BCS strategy in
drug development will lead to significant direct and indirect savings for pharmaceutical companies.
Usage of in silico tools for modeling of the properties underlying the BCS can
be used for fast preliminary screening of new compounds to determine their positions in the BCS. Nowadays a lot of different models and systems for prediction of
bioavailability, permeability, solubility, etc., are available. But all of them lack the
prediction accuracy. There are two ways to overcome this problem: (1) improve
14 Quantitative Structure-Property Relationship Analysis …
Grass Model describes fluid movement (emptying and transit) in the GI tract
and calculates the drug absorption in each compartment (stomach, duodenum, jejunum, ileum, and colon) over time based primarily on three parameters-solubility,
permeability, and tissue surface area. This model was shown to predict plasma concentration time profiles including the AUC, C max , and t max for ketorolac (BCS 1)
and gancyclovir (BCS 3) well. The software IDEA™ was developed based upon
compartmental models (IDEA™ is not currently available). By using IDEA™, the
fractions of dose absorbed for atenolol (BCS 3), naproxen (BCS 2), and gancyclovir
(BCS 2) in animals and humans were successfully predicted [86]. Similar to GastroPlus™, factors including dose, solubility, and permeability are considered. However, IDEA™ does not take first pass metabolism and drug transport into account.
14.5 Conclusions
Sufficient intestinal absorption of orally administered drugs from the gastrointestinal tract is one of the prerequisites for successful oral drug therapy. It is generally
accepted that the main barrier interrupting drug absorption is formed by the intestinal epithelium and several routes can be followed to pass it. Passive transport often
occurs through the cell membrane of the enterocytes (transcellular transport), this
is the predominant transport route for hydrophobic drugs. Another passive route is
transport via the tight junctions between the enterocytes, i.e., paracellular transport.
Hydrophilic compounds are mostly transported via the paracellular route. Finally,
carrier-mediated transport (influx or efflux) can be observed. Intestinal drug absorption is controlled by dissolution rate and solubility, determining how fast a drug
reaches maximum concentration in the lumenal intestinal fluid, and permeability
coefficient, which relates to the rate at which dissolved drug will cross the intestinal
wall to reach the portal blood circulation. Determination of the dissolution, solubility (at different pH values), and permeability properties of drug candidates can thus
provide information about their absorption potential, and thus allows evaluation of
the compounds according to BCS. The aim of the BCS is to provide a regulatory
tool for replacing certain bioequivalence studies by accurate in vitro dissolution
tests. This will certainly reduce costs and time in the drug development process,
both directly and indirectly, and reduce unnecessary drug exposure in healthy subjects, which is normally the study population in bioequivalence studies. The BCS is
today only intended for oral immediate-release products that are absorbed throughout the intestinal tract. It has been reported that an application of a BCS strategy in
drug development will lead to significant direct and indirect savings for pharmaceutical companies.
Usage of in silico tools for modeling of the properties underlying the BCS can
be used for fast preliminary screening of new compounds to determine their positions in the BCS. Nowadays a lot of different models and systems for prediction of
bioavailability, permeability, solubility, etc., are available. But all of them lack the
prediction accuracy. There are two ways to overcome this problem: (1) improve