462
N. Ya. Golovenko et al.
14.1 Introduction
During the last few years, the role of pharmacokinetic (absorption, distribution, metabolism, and elimination, i.e., ADME) properties in the drug research and development increased dramatically [1–3]. Oral bioavailability is one of these ADME
components that have been widely studied. Screening of absorption ability is an
important part of assessing oral bioavailability and attracts efforts from industry and
academia. Although plethora of in vitro and in vivo ADME screening methods have
been applied to boost drug discovery process in pharmaceutical industry, this process
is still resource-intensive and time-consuming. The prediction of oral bioavailability
is very challenging because bioavailability is a complex function of many biological
and physico-chemical factors, such as dissolution in the gastrointestinal tract, intestinal membrane permeation, intestinal and hepatic “first-pass” metabolism, etc.
Although ADME assays have been the gold standards in pharmacokinetics, there
are additional tests that should be incorporated, since they play a key role in drug
discovery and further development. Liberation and dissolution of the drug from the
pharmaceutical form is a key parameter in bioequivalence studies The solubility and
permeability of a drug are considered to be the most important properties that determine absorption and the influence of these two properties on the extent of absorption
from the intestinal tract has received considerable attention [4–6]. An experimental system for classification of drugs based on their aqueous solubility and membrane permeability was implemented recently by the Food and Drug Administration
(FDA). It was named as the biopharmaceutics classification system (BCS). BCS
was originally implemented to waive clinical studies of generic high-permeability/
high-solubility drugs. The original BCS categorizes drugs into four different classes
based on combinations of high/low solubility and high/low permeability [7]. As an
alternative to experimental measurements, the in silico prediction of ADME properties is very attractive, because it provides an inexpensive and highthroughput way to
assess the ADME properties of a molecule prior to synthesis and biological testing.
The purpose of this monograph is to discuss basic principles associated with the
process of drug absorption. Special attention will be given to the use of the BCS
as a predictive tool for identifying compounds whose absorption characteristics
may be sensitive to physiological and formulation variables. Investigation of drug
absorption requires a fundamental understanding of the molecular properties that
determine passive membrane transport. These properties will be briefly discussed
in the following section.
14.2 Methodology of the Biopharmaceutics Classification
System (BCS)
The rate and extent of drug absorption from the gastrointestinal (GI) tract are very
complex and affected by many factors. These include physico-chemical factors
(solubility, lipophilicity, stability, pK a , polar surface area, presence of hydrogen
N. Ya. Golovenko et al.
14.1 Introduction
During the last few years, the role of pharmacokinetic (absorption, distribution, metabolism, and elimination, i.e., ADME) properties in the drug research and development increased dramatically [1–3]. Oral bioavailability is one of these ADME
components that have been widely studied. Screening of absorption ability is an
important part of assessing oral bioavailability and attracts efforts from industry and
academia. Although plethora of in vitro and in vivo ADME screening methods have
been applied to boost drug discovery process in pharmaceutical industry, this process
is still resource-intensive and time-consuming. The prediction of oral bioavailability
is very challenging because bioavailability is a complex function of many biological
and physico-chemical factors, such as dissolution in the gastrointestinal tract, intestinal membrane permeation, intestinal and hepatic “first-pass” metabolism, etc.
Although ADME assays have been the gold standards in pharmacokinetics, there
are additional tests that should be incorporated, since they play a key role in drug
discovery and further development. Liberation and dissolution of the drug from the
pharmaceutical form is a key parameter in bioequivalence studies The solubility and
permeability of a drug are considered to be the most important properties that determine absorption and the influence of these two properties on the extent of absorption
from the intestinal tract has received considerable attention [4–6]. An experimental system for classification of drugs based on their aqueous solubility and membrane permeability was implemented recently by the Food and Drug Administration
(FDA). It was named as the biopharmaceutics classification system (BCS). BCS
was originally implemented to waive clinical studies of generic high-permeability/
high-solubility drugs. The original BCS categorizes drugs into four different classes
based on combinations of high/low solubility and high/low permeability [7]. As an
alternative to experimental measurements, the in silico prediction of ADME properties is very attractive, because it provides an inexpensive and highthroughput way to
assess the ADME properties of a molecule prior to synthesis and biological testing.
The purpose of this monograph is to discuss basic principles associated with the
process of drug absorption. Special attention will be given to the use of the BCS
as a predictive tool for identifying compounds whose absorption characteristics
may be sensitive to physiological and formulation variables. Investigation of drug
absorption requires a fundamental understanding of the molecular properties that
determine passive membrane transport. These properties will be briefly discussed
in the following section.
14.2 Methodology of the Biopharmaceutics Classification
System (BCS)
The rate and extent of drug absorption from the gastrointestinal (GI) tract are very
complex and affected by many factors. These include physico-chemical factors
(solubility, lipophilicity, stability, pK a , polar surface area, presence of hydrogen