Overview of factors affecting oral drug absorption
ABSTRACT This article provides an overview of variables that can affect drug absorption following oral administration in recent years, including both physicochemical properties of the drug and physiological factors of the body. The oral absorption of a drug is a complex process depending upon these factors and their interactions with each other. Solubility and permeability are considered as the major physicochemical factor that affect the rate and extent of oral drug absorption, moreover other physicochemical properties always show their effects to drug absorption via affecting solubility and permeability. In this regard, the Biopharmaceutics Classification System is proved to be a successful predictive tool for drug development. Oral drug bioavailability can also be markedly influenced by physiological factors, such as gastrointestinal pH, gastric emptying, small intestinal transit time, bile salt, absorption mechanism and so on. Thus by understanding the physicochemical properties of a compound and by recognizing the physiological processe affecting drug absorption, also with the awareness of a drug's BCS characteristics, pharmaceutical scientists can better predict drug absorption and develop formulations that can maximize drug bioavailability.
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ABSTRACT: PURPOSE: Design of biorelevant test setups mimicking the physiological conditions experienced by drugs after oral administration along the passage through the mouth and the GI tract for the in vitro evaluation of diclofenac exhibiting multiple-peak phenomenon during absorption. METHODS: The biorelevant models simulated successively saliva (SSF, pH 6.2-6.75-7.4, 5 mL, 3 min), gastric (SGF-FaSSGF, pH 1.2-1.6, 50-250 mL, 30 min) and intestinal (FaSSIF, pH 6.8, 250 mL, 60 min) fluids. Applying these models, diclofenac free acid and its sodium/potassium salt were comparatively evaluated for dissolution and further characterized by HPLC, optical morphogranulometry, DSC and PXRD to elucidate peculiar behaviors. RESULTS: Diclofenac salts almost completely dissolved in SSF and showed a transitional dissolution pattern before complete precipitation in SGF/FaSSGF. This peculiar pattern correlated with simultaneous chemical modification and formation of agglomerates. With low dissolution in SSF and almost immediately complete precipitation, these behaviors were not observed with diclofenac free acid. Distinct diclofenac features were strongly determined by pH-modifications after oral administration. CONCLUSIONS: The multiple-peak phenomenon observed after administrating a solution, suspension or dispersible formulation of diclofenac salts are likely caused by drug precipitation and agglomeration in the stomach leading to irregular gastric-emptying. Diclofenac free acid may provide more reliable in vivo features.Pharmaceutical Research 03/2013; · 4.74 Impact Factor
Asian Journal of Drug Metabolism and Pharmacokinetics
Copyright by Hong Kong Medical Publisher
Overview of factors affecting oral drug absorption
Nai-Ning Songa,b, Shao-Yu Zhangb, Chang-Xiao Liua
aTianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of
Pharmaceutical Research, Tianjin, 300193, China
bDepartment of Pharmacology, College of Basic Medical Sciences, Tianjin Medical University, Tianjin
This article provides an overview of variables that can affect drug absorption following oral administration
in recent years, including both physicochemical properties of the drug and physiological factors of the
body. The oral absorption of a drug is a complex process depending upon these factors and their
interactions with each other. Solubility and permeability are considered as the major physicochemical
factor that affect the rate and extent of oral drug absorption, moreover other physicochemical properties
always show their effects to drug absorption via affecting solubility and permeability. In this regard, the
Biopharmaceutics Classification System is proved to be a successful predictive tool for drug development.
Oral drug bioavailability can also be markedly influenced by physiological factors, such as gastrointestinal
pH, gastric emptying, small intestinal transit time, bile salt, absorption mechanism and so on. Thus by
understanding the physicochemical properties of a compound and by recognizing the physiological
processe affecting drug absorption, also with the awareness of a drug’s BCS characteristics,
pharmaceutical scientists can better predict drug absorption and develop formulations that can maximize
oral drug absorption; bioavailability; the Biopharmaceutics Classification; physicochemical properties;
Paper ID 1608-2281-(2004)-0403-00167-10
Received May 29, 2004
Accepted August 10 , 2004
SSN 1608-2281 2004; 4(3): 167-176
The oral absorption process of drug from a
pharmaceutical dosage form is very complex.
However, the major steps occurring during oral drug
absorption can be regarded as part of a serial process
(Fig.1): (1) The dissolution of the drug from the
dosage form；(2) The solubility of drug as a function
of its physicochemical characteristics；(3) The drug’s
effective permeability to the intestinal mucosa；and
(4) The drug’s presystemic metabolism. 
*This work was a part of National 863 plan No.2003AA2Z374D
Correspondence to Prof Chang-Xiao Liu, Tianjin national Key
Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin
Institute of Pharmaceutical Research, 308 Anshan West Road,
Tianjin, 300193, China
Tel: +86-22-23006863; Fax: +86-22-23006860
There are many factors that may affect the above
processes, and finally affect the rate and extent of
oral drug absorption. These factors can be divided
into three categories.[2,3] The first category represents
physicochemical properties of a drug, including
solubility, intestinal permeability, pKa, lipophilicity,
stability, surface area, particle size and so on. The
second category comprises physiological factors,
such as gastrointestinal pH, gastric emptying, small
intestinal transit time, bile salt, absorption mechanism
and so on. The third category contains dosage form
factors, such as solution, capsule, tablet, suspension
and so on.
The purpose of this article is to discuss factors
affecting oral drug
physicochemical properties of the drug, physiological
factors of the body, and some effects of formulation.
Also the Biopharmaceutics Classification System
(BCS) is introduced in the article as a predictive tool
for identifying compounds whose oral absorption
may be sensitive to physicochemical and
Fig 1. Oral absorption of drugs from a pharmaceutical drug product
The Biopharmaceutical Classification System
The Biopharmaceutics classification system
(BCS) has been one of the most significant
prognostic tools created to promote product
development in recent years. It is a scientific
framework for classifying drug substances based on
their aqueous solubility and intestinal permeability
characteristics, which will substantially facilitate drug
product selection and approval process for a large
group of drug candidates. The goal of the BCS is to
function as a tool for developing in vitro dissolution
specifications for drug products that are predictive of
their in vivo performance.
According to the BCS, drug substances are classified
Class 1: High Solubility-High Permeability:
generally very well-absorbed compounds
Class 2: Low Solubility-High Permeability:
exhibit dissolution rate-limited absorption
Class 3: High Solubility-Low Permeability:
exhibit permeability rate-limited absorption
Class 4: Low Solubility-Low Permeability: very
poor oral bioavailability.
The Class Boundaries:
? A drug substance is considered HIGHLY
SOLUBLE when the highest dose strength is soluble
in≤250 ml water over a pH range of 1 to 7.5.
? A drug substance is considered HIGHLY
PERMEABLE when the extent of absorption in
humans is determined to be ≥ 90% of an
administered dose, based on mass-balance or in
comparison to an intravenous reference dose.
? A drug product is considered to be
RAPIDLY DISSOLVING when ≥ 85% of the
labeled amount of drug substance dissolves within 30
minutes using USP apparatus I or II in a volume of
≤900 ml buffer solutions.
The pH-solubility profile of the test drug
substance should be determined in aqueous media
with a pH in the range of 1-7.5 using traditional
shake-flask method as well as acid or base titration
methods. A sufficient number of pH conditions
should be evaluated to accurately define the
pH-solubility profile. Concentration of the drug
substance in selected buffers (or pH conditions)
should be determined
stability-indicating assay that can distinguish the drug
substance from its degradation products.
The permeability class of a drug substance can
be determined in human subjects using mass balance,
absolute BA, or intestinal perfusion approaches: 1.
Pharmacokinetic Studies in Humans: a. Mass Balance
Studies b. Absolute Bioavailability Studies; 2.
Intestinal Permeability Methods: The following
methods can be used to determine the permeability of
a drug substance from the gastrointestinal tract: (1) in
vivo intestinal perfusion studies in humans; (2) in
vivo or in situ intestinal perfusion studies using
suitable animal models; (3) in vitro permeation
studies using excised human or animal intestinal
tissues; or (4) in vitro permeation studies across a
monolayer of cultured epithelial cells; 3. Instability in
the Gastrointestinal Tract: determining the extent of
absorption in humans based on mass balance studies
using total radioactivity in urine does not take into
consideration the extent of degradation of a drug in
the gastrointestinal fluid prior to intestinal membrane
using a validated
Dissolution testing should be carried out in USP
Apparatus I at 100 rpm or Apparatus II at 50 rpm
using 900 mL of the following dissolution media: (1)
0.1 N HCl or Simulated Gastric Fluid USP without
enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer
or Simulated Intestinal Fluid USP without enzymes.
For capsules and tablets with gelatin coating,
Simulated Gastric and Intestinal Fluids USP (with
enzymes) can be used. When comparing the test and
reference products, dissolution profiles should be
compared using a similarity factor (f2). The similarity
factor is a logarithmic reciprocal square root
transformation of the sum of squared error and is a
measurement of the similarity in the percent (%) of
dissolution between the two curves. Two dissolution
profiles are considered similar when the f2 value is
By understanding the relationship between a
drug’s absorption, solubility,
characteristics, it is possible to define situations when
in vitro dissolution data can provide a surrogate for in
vivo bioequivalence assessments,that is to find under
which circumstances dissolution testing can be
prognostic for in vivo performance.
For immediate release formulations of Class 1
drugs, in dissolution tests, the only need is to verify
that the drug is indeed rapidly released from the
dosage form under mild aqueous conditions.
For Class 2 drugs, in order to establish a strong
correlation between the results of dissolution tests
and the in vivo absorption rate, it is necessary to
reproduce the conditions extant in the gastrointestinal
tract following administration of the dosage form as
possible. Adequate comparison of formulations for
Class 2 drugs requires dissolution tests with multiple
sampling times in order to characterize the release
profile, and in some cases the use of more than one
dissolution medium may also be worth considering.
Class 3 drugs are also defined as being rapidly
dissolved as Class 1 drugs, then the test criterion
should be that the formulation can release the drug
under mild aqueous
predetermined time. Besides, the duration of the
dissolution test should be at least as stringent for
Class 3 drugs as for Class 1 drugs to try to maximize
the contact time between the dissolved drug and the
absorbing mucosa, and further the bioavailability of
As for Class 4 drugs, which are generally
conditions within a
considered poorly absorbed, special attentions should
be paid on the formulation to avoid additional,
negative influence on both the rate and extent of drug
absorption caused by poor formulation.
solubility and permeability
Solubility and intestinal permeability are the
major physicochemical factors that affect the rate and
extent of absorption of an oral drug product.
Moreover, these two factors also closely interrelate
with many other influential factors, such as
lipophilicity, hydrophilicity, molecular size, polar van
der Walls surface area, and so on, and thus act as the
“final bridge” toward drug absorption. Therefore,
making clear factors affecting solubility and
permeability may be significantly important in drug
product development and approval process for a large
group of drug candidates.
The first requirement for absorption is
dissolution of the active compound. Only compound
in solution is available for permeation across the
gastrointestinal membrane. Solubility has long been
recognized as a limiting factor in the absorption
process. By definition, solubility is the extent to
which molecules from a solid are removed from its
surface by a solvent. Aqueous solubility can be
estimated by determining the ability of a drug to
partition from lipid to aqueous environments, which
is dependent on the ionization of drug tested. Most
drugs are weakly acidic or weakly basic compounds
that cannot ionize completely in aqueous media,
while only partly ionize. Since drug ionization are
greatly dependent on the solvent pH, the above
partition behavior is often considered as a function of
solvent pH, and pKa is often used as a parameter
describing a compound’s dissolution characteristic.
In general, ionized drugs tend to exhibit far greater
aqueous solubility than the un-ionized counterpart.
As a result, the rate of solute dissolution in aqueous
media can be markedly affected by the pH of the
To illustrate the effect of PH on drug ionization,
one can seek to a rearrangement of the Henderson-
% un-ionized =
1 + antilog(pH-pKa)
% un-ionized =
1 + antilog(pKa-pH)
Weakly acidic drugs dissolve faster when
solvent PH is relatively high(when more drug exists
in its ionized form), while tend to have a slower
dissolution rate at lower solvent pH (when more drug
exists in its un-ionized form); on the contrary, weakly
basic drugs dissolve faster when solvent pH is
relatively low, and tend to have a slower dissolution
at higher solvent PH. When solvent PH is equal to
drug pKa, both weakly acidic drugs and weakly basic
drugs exhibit the lowest solubility. Based on the
above reason, by increasing the proportion of drug
existing in its un-ionized state, meals that elevate
gastric pH can decrease the dissolution of a weak
base. For example, weak bases such as indinavir
(with pKa of 3.7 and 5.9) are expected to precipitate
when gastric PH is elevated during a meal, resulting
in a significant reduction in AUC and Cmax values in
fed versus fasted human subjects. Conversely, the
same meal can increase the dissolution rate of a weak
acid by increasing the proportion of drug existing in
its ionized state, thereby making it more water
Besides the above classic method using solvent
pH and drug pKa to access drug solubility, several
attempts have been made to estimate solubility from
molecular structure, that is to find molecular
properties that affect drug solubility. A compound’s
aqueous solubility, as measured by its propensity to
distribute between octanol and water, is a function of
its ability to form hydrogen bonds with the water
molecule. Generally, aqueous solubility is directly
proportional to the number of hydrogen bonds that
can be formed with water. Delaney. used linear
regression against nine molecular properties. The
most significant parameter
logP(octanol), followed by molecular weight,
proportion of heavy atoms in aromatic systems, and
number of rotatable bonds. The model performed
consistently well across three validation sets,
predicting solubilities within a factor of 5-8 of their
measured values, and was competitive with the
well-established “General Solubility Equation” for
medicinal/agrochemical sized molecules.
Although lipid/water partitioning is often used to
describe drug solubility, there is some evidence that
solubility may better be described by the compound’s
dynamic energy properties. Determination of
solubility parameter of a drug is a most common
approach to quantify the cohesive energy for a drug,
which is defined as the amount of energy required to
separate the drug into its constituent atoms or
molecules. The result showed that negative
correlation was both evident between solubility
parameter values and the extent of oral absorption,
and between the number of H-bonding acceptor
groups in a compound and the extent of oral
absorption. Whereas, when ClogP values were used
in comparison, no obvious correlation existed.
Permeability is another important factor in
achieving desirable oral bioavailability. The above
critical property of permeability should contribute to
the correspondingly unique way about how
substances (including drugs) “travel through” cellular
membranes. So to discuss physicochemical properties
affecting permeability, one need first get to know the
structure of cellular membranes and how drugs pass
through these membranes (Fig 2).
In the Fluid Mosaic model, the structure of
cellular membranes is described as an interrupted
phospholipid bilayer capable of both hydrophilic and
hydrophobic interaction. The two most common
ways for the absorption of drugs are passive transfer
by diffusion across the lipid membranes and passive
diffusion through the aqueous pores at the tight
junctions between cells. These two processes are
referred to as transcellular and paracellular absorption,
respectively. The ability of a drug to diffuse across
the lipid core of the membrane is clearly dependent
on physicochemical properties. Thus transcellular
absorption is the predominant pathway for more
lipophilic molecules. In contrast, the paracellular
route of absorption is particularly important in
determining the efficiency of absorption of
hydrophilic compounds, the restricted diameter of the
aqueous pores(typically 3 to 6 Å in humans)means
that molecular size also becomes important in the
ability of polar molecules to utilize this pathway,
which is thought to be possible only for small
hydrophilic molecules (MW < 200) [15,16,17].
Fig 2. GI membrane transport. The transport through the enteroyte barrier can be generally divided into active, passive and
specialized transport and into a paracellular and transcellular route
Knowing about these particular characteristics
of cellular membranes, several related factors of
drugs such as lipophilicity, hydrophilicity, molecular
size, polar van der Walls surface area and molecular
flexibility and so on should be considered when
accessisng drug permeability, modifying structure
properties and finally designing more effective
alternatives. Therefore the relationship between the
above affecting properties and intestinal permeability
are discussed as follows.
Because of the lipid nature of cell membranes, a
molecule’s lipophilicity has long been considered as
an important factor in drug design. Lipophilicity is
generally quantified wexperimentally by measuring
the log10 of the partition coefficient between
n-octanol and water (log P). The relationship between
log P and permeability is non-linear, with decreases
in permeability at both low and high log P. These
non-linearities are theorized to be due to: (1) the
limited diffusion of poorly lipophilic molecules into
the phospholipid cell membrane, and (2) the
preferential partitioning of highly
molecules into the phospholipid cell membrane,
preventing passage through the aqueous portion of
Dynamic surface area properties also have
effects on drug permeability. The polar surface area
(PSA) of a molecule is defined as the area if its van
der Walls surface thar arises from oxygen or nitrogen
atoms or hydrogen atoms attached to oxygen or
nitrogen atoms. The “dynamic” PSA (PSAd) is a
Boltzmann-weighted average value computed from
an ensemble of low-energy conformers obtained by a
detailed conformational search. Palm K and
co-workers correlated the dynamic surface area
properties of drug molecules with drug absorption.
Good inverse linear correlations between the dynamic
polar surface area and permeability coefficients in
monolayers of human intestinal epithelial Caco-2
cells and existed rat intestine were obtained,
indicating that the dynamic polar surface area is an
important factor in passive trans-cellular transport
across cell membrane.
The hydrogen bonding ability of a molecule (an
estimate of its hydrophilicity) is another important
property for cellular membrane permeability. In Veber.
DF and co-workers’ study, Hydrogen bond donors
were taken as any heteroatom with at least one
bonded hydrogen. Hydrogen bond acceptors were
taken as any heteroatom without a formal positive
charge. Higher oral bioavailability is found to be
associated with lower hydrogen bond counts.
Besides, permeability is also affected by several
other factors and is the function of multi-effects of all
these factors. Specifically, higher oral bioavailability
is indeed associated with lower molecular weight,
which is a surrogate for other properties, such as
polar surface area and hydrogen bond count, as well
as rotatable bonds (defined as any single bond, not in
a ring, bound to a nonterminal heavy atom). With the
increasing of molecular weight, these properties also
tend to increase.
Also properties of the solute may have effects on
drug permeability. Goodwin and co-workers
demonstrate that both hydrogen-bond potential and
volume of the solutes contribute to permeability and
suggests that the nature of the permeability–limiting
microenvironment within the cell depends on the
properties of a special solute.
The successful functioning of oral medication
depends primarily on how the gastrointestinal (GI)
tract processes drugs and drug delivery systems.
Many factors are involved in oral drug delivery, the
measured oral bioavailability of a particular drug can
be broken into components that reflect delivery to the
intestine (gastric emptying, PH, food), absorption
from the lumen (dissolution, lipophilicity, particle
size, active uptake), intestinal metabolism (phase Ⅰ
and/or phase Ⅱ enzymes), active extrusion (drug
efflux pumps) and finally first-pass hepatic extraction.
All these factors play an important role in the
performance of orally administered dosage forms,
and to understand how they affect oral drug
absorption can greatly contribute to the drug
Principally, the rate of release of a drug from a
dosage form within the GI tract should be considered.
Drug dissolution, especially for poorly soluble drugs,
is dependent upon the volume of juices available in
the gastrointestinal tract, which are from the volume
of coadministered fluids, secretions and water flux
across the gut wall. The volume of intestinal juices
is important to estimate if a single dose can
theoretically dissolve within the gut passage.
The presence of bile may improve the
bioavailability of poorly water soluble drugs by
enhancing the rate of dissolution and/or solubility.
Bile salts can increase drug solubility via micellar
solubilization. The increase in the rate of dissolution
also may occur via a decrease in the interfacial
energy barrier between solid drug and the dissolution
media (via enhanced wetting), leading to an effective
increase in surface area. For example, in Galia E
and co-workers’ study, dissolution of Class Ⅱ
drugs (low solubility-high permeability) are proved to
be in general much more dependent on the medium
(including the presence of bile salt) than class I drugs
(high solubility-low permeability, such as dissolution
of mefenamic acid from a capsule formulation is
dependent on bile salt concentration. Bakatselou and
co-workers studied the ability of sodium
taurocholate to increase the initial dissolution rate of
five steroids (hydrocortisone,
betamethasone, and dexamethasone, danazol), the
result showed that at bile salt concentrations
representative of the fasted state, wetting effects
predominated over solubilization effects for all
compounds. While at
concentrations typical of the fed state, for the more
lipophilic danazol, the increase in solubility was the
predominant factor. Also the extent to which bile salts
can enhance the solubility of a drug can be predicted
based on the physicochemical properties of the
compound, that is the increase in solubility as a
function of bile salt concentration can be estimated
on the basis of the partition coefficient and aqueous
solubility of the compound.
Gastric emptying and Intestinal transit time
Furthermore, gastric emptying and GI transit
time are important parameters for the onset and the
degree of drug absorption. It is well known that the
gastric emptying rate is an important factor affecting
the plasma concentration
administered drugs, and the intestinal transit rate also
has a significant influence on the drug absorption,
since it determines the residence time of the drug in
the absorption site. The reason why the residence
time is also a critical factor for drug absorption is that
there is the site difference in absorbability for some
drugs. Lipka and co-workers demonstrated the
significant effect of gastric emptying on the rate and
extent of celiprolol absorption and its role with
respect to influence the occurrence of double
peaks.Based on the assumption that gastric emptying
and intestinal transit rates will vary directly with the
strength of the contractile activity characteristic of
the fasted state motility cycle. Oberle and
co-workers concluded that variable gastric
emptying rates due to the motility cycle can account
for plasma level double peaks. Furthermore, variable
gastric emptying rates combined with the short
plasma elimination half-life and poor gastric
absorption of cimetidine can be the cause of the
frequently observed plasma level double peaks.
Marathe pH and co-workers assessed the effect of
the higher bile salt
profile of orally
altered gastric emptying and gastrointestinal motility
on the absorption of metformin in healthy subjects.
Results showed that AUC(0,infinity) and UR% (percent
dose excreted unchanged in urine) generally
increased with increase in gastric emptying time and
small intestinal transit times, that is the extent of
metformin absorption is improved when the
gastrointestinal motility is slowed. Kimura and
Gastrointestinal (GI)-Transit-Absorption Model in
the prediction method
concentration-time profile of N-methyltyramine
(NMT). Estimating permeability of each GI segment
to NMT indicated that this compound is absorbed
mainly from the small intestine and that permeability
to NMT is largest in the duodenum and jejunum.
However, the contribution of this region to the total
absorption in vivo is found to be small. The
substantial absorption sites in vivo were suggested to
be the regions from lower jejunum to lower ileum,
which have longer residence time than duodenum and
upper jejunum, thus the substantial absorption is a
function of longer residence time.
The liver is the major organ for drug metabolism,
thus the prediction of human hepatic clearance is of
great value in study factors affecting oral drug
absorption. Lin and co-workers provided an
excellent discussion of factors that can affect the
clearance, which can further affect the overall
bioavailability of drugs. The hepatic clearance was
described as follows:
= (Q Qh h・ f ・ fB B・ CL・ CLint,h
= (f fB B・ CL ・ CLint,h
where Qh is the liver blood flow, CLint,h is hepatic
intrinsic clearance, fB is the unbound fraction of drug
in the blood, and EH is the hepatic extraction ratio,
which is defined as the fraction of the drug entering
liver that is metabolized during its transit through the
liver. Therefore, only a portion (1-EH) of the dose
passed through the liver will escape metabolism.
During drug absorption, the extraction ratio (EH) also
is termed “first-pass” or “presystemic” elimination in
liver, which is also take place in other organs, such as
Martinez and co-workers transform the above
CL CLH H = Q = Qh h・ E ・ E, and
for the plasma
H = (
H = (
int,h) )/ /(Q
h+ f fB B・ CL
h+ f fB B・ CL
int,h) )/ /(Q
E = [(fE = [(fb b・ CL
when Qh>>fb· CLint,, then CLH = Qh · [(fb· CLint)/(Qh+
fb· CLint)], which tends toward
f fb b・ CL・ CLint
・ Qh h / Q/ Qh h = f= fb b・ CL・ CLint
・ 1= fb b・ CL
Conversely, when Qh << fb· CLint,, then CLH-Qh.
For high E compounds, CLH is said to be blood flow
limited (i.e., Qh<< fb· CLint,). In other words, CLH
will be affected by anything that can alter Qh (or
Qh-splancnic for oral first-pass effects). In these cases,
factors altering intrinsic clearance (CLint), such as
drug-drug interactions, should have minimal impact
on CLH. alternatively, for low E drugs, CLH-fb· CLint.
in this situation, any factor that alter fb, Vmax, or KM
can markedly affect CLH. An example of these
interrelationships is seen with the interaction between
indinavir (oral or intravenous administration) and
ketaconazole (oral administration).
It is also quite important to consider small
intestine as a potential site of drug metabolism.
Substantial drug loss can occur via intestinal efflux
mechanisms, gut wall metabolism (both PhaseⅠ and
Phase Ⅱ), and the degradation within the gut lumen.
The cytochrome P450s (CYPs) are the major
enzymes involved in the metabolism of drugs. Some
of the CYP isoforms present in the liver are also
expressed in the gut wall epithelium, the major one is
CYP3A4, which in the small intestine approaches
50% of the hepatic level, and act as the major phase I
drug metabolizing enzyme in humans. Both CYP3A4
and the multidrug efflux
P-Glycoprotein (P-gp), are present at high levels in
the villus tip enterocytes of the small intestine, the
primary site of absorption for orally administered
drugs. These proteins are induced or inhibited by
many of the same compounds and demonstrated a
broad overlap in substrate and inhibit specificities,
suggesting that they act as a concerted barrier to dug
absorption. Coadministration of cyclosporine with
rifampin, an inducer of both CYP3A4 and P-gp,
increases cyclosporine clearance, decreases its half-
life, bioavailability (Foral) and Cmax. Conversely,
ketoconazole, a CYP3A4 and P-gp inhibitor,
decreases cyclosporine clearance, increases its half
life, bioavailability (Foral) and Cma.
co-workers performed a study in intestinal and
vascular access ported rabbits to quantify and
differentiate the components of intestinal and hepatic
first pass extraction (i.e., metabolism and secretion)
・ CLintint)/(Q)/(Qh h + f + fb b・ CL ・ CLintint)] )]
int・ 1= f・ CLintint
pump, MDR or
 Sinko and
of saquinavir (SQV) mediated by P-gp and CYP3A.
In the presence of CYP3A and P-gp inhibitors, the
BA of SQV increased 2- to 11-fold. Based on a
relatively unchanged Cmax but prolonged Tmax and
t(1/2), P-gp and CYP3A inhibition appeared to alter
SQV disposition (i.e., enhanced oral bioavailability
by diminishing SQV elimination and by increasing its
net intestinal absorption). In conclusion, the current
results substantiate the role of the liver and, for the
first time, experimentally establish an important role
for the intestine in the net absorption and disposition
metabolized in the gut lumen by digestive enzymes or
by activity of the gut microflora. The former can
decrease bioavailability of chloramphenicol when
administered in some species due to microbial
degradation in the gut, while the presence of gut
microflora may enhance drug bioavailabilty by
promoting biliary recycling of compounds such as
ouabain, digoxin, and steroid hormones.
The effect of food on drug oral bioavailability is
extremely complex. Based on the physicochemical
properties of the compounds, physiological changes
induced by the intake of food mainly happen in
slowing of gastric emptying rate and the increase in
The pH differences in the contents of the upper
GI tract between fed and fasted states can influence
the dissolution and absorption of weakly acidic and
basic drugs. Elevation of gastric pH following a meal
may enhance the dissolution of a weak acid in the
stomach but inhibit that of a weak base. Furthermore,
food inhibits the rate of gastric emptying, prolonged
retention in the stomach may increase the proportion
of drug that dissolves prior to passage into the small
intestine, which is the primary site of drug
Elevated gastric pH may afford enhanced
bioavailability of acid-labile drugs such as penicillin,
erythromycin, and digoxin. For example, under acidic
conditions, digoxin is hydrolyzed to the digoxigenin
aglycone derivative, which has reduced pharmaco-
For ionic drugs, the fraction of drug available
for the absorption may be altered by changing pH
values, thus affect the intestinal permeability of the
drug. Besides, Ph changing can affect the dissolution
also be extensively
of some formulations, such as some coating materials
used on tablets which are PH dependent, or some
formulation excipients can also cause drug release to
vary with pH, or impact on the permeability of
insoluble film coatings used to provide controlled
release of medicaments as well as on the overall
dissolution and drug release patterns from various
matrix-based sustained-release formulation.
The Noynes-Whitney equation describes the
variables that can affect drug dissolution:
dm/dt=(D·S/V·h)(Cs - Ct )
where dm/dt is the dissolution rate; D is the diffusion
coefficient; S is the surface area; h is the thickness of
the dissolution film adjacent to the dissolving surface;
Cs is the saturation solubility of the drug molecule; Ct
is the concentration of the dissolved solute; and V is
the volume of the dissolution medium.
Among these factors, two variables that can be
controlled by formulation are surface area and
solubility. Increasing the surface area (S) of a drug
particle can enhance the dissolution rate of the drug.
Drug particle size can be reduced to increase the
effective surface area available for dissolution, which
can be achieved by using wetting agents that lower
the surface tension of the dissolution medium.
However, since the amount
surface-active agents needed to enhance in vivo drug
dissolution rate may have effects on drug safety, these
agents are not generally
formulations. Drug particle is also important in
determining the dissolution behavior of a drug. The
shape factor for any non-isometric particle cannot be
considered to be constant over the dissolution event,
as is commonly assumed. This change has an
appreciable effect on the dissolution behavior of
crystals (particularly of significance for elongated
shapes like needles and platelets). Sometimes
modification of surface morphology of drug particle
can improve its stability . The solubility of weakly
acidic and weakly basic drugs can be modified by
using buffer agent to slightly change the surrounding
pH. However, solubility differences between drug
and buffer must be considered to avoid their relative
dissolution rates preclude maintenance of the
“microenvironment” during the dissolution process.
Besides buffering agents, some excipients are known
to have effects on physiological conditions, such as
of the above
used in product
decrease GI transit time, affect membrane
permeability and inhibit efflux pumps.[43,44]
Drug absorption is a highly complex process,
which is based on both physicochemical properties of
the drug and physiological conditions of the body.
Therefore, in years scientists have been striving for
improving the above two aspects to achieve desirable
drug absorption, thus to screen out, optimize a large
number of drug candidates and consequently promote
drug development. In particular, solubility and
permeability are the most important physicochemical
properties affecting drug absorption; furthermore
most other physicochemical properties (such as
lipophilicity, pKa, molecular size, logP value,
hydrogen bonding dynamics, and so on) are all
correlated to solubility and permeability, and through
their positive or negative effects on solubility and
permeability to finally affect drug bioavailability.
Therefore, solubility and permeability can be
considered to act as the “final bridge” toward drug
absorption. On the other hand, physiological
variables also can markedly affect the absorption
characteristics of a drug. Generally drugs are
absorbed in un-ionized state, which is dependent
upon GI pH; also the changing of gastric emptying
rate and intestinal transit time can affect drug
absorption. Besides, drug may be metabolized by
enzymes in liver and intestine, and by activity of the
gut microflora. Therefore, the successful functioning
of oral drug not only relates to the drug
dependent upon the delivery process in vivo, which is
a function of many physiological factors. Moreover,
pharmaceutists have been exerting to improve oral
drug bioavailability through the invention and
application of new
improvement in formulation may also depend on
their effects to physicochemical and physiological
factors to affect drug absorption. Such as, increasing
surface area of drug particle actually means changing
its physicochemical properties, while the purposes of
using some excipients and surfactants is to affect the
physiological factors. Thus, by understanding the
physicochemical properties of a compound and by
recognizing the physiological processed affecting
drug absorption, also with the awareness of a drug’s
BCS characteristics, pharmaceutical scientists can
but also greatly
formulations that can maximize drug bioavailability.
In this review, we discussed only some factors
affecting drug absorption,
characteristics, physiological properties, formulation
and food effects. Other factors, such as patient’s
conditions, age, metabolism enzymes, administration
time, drug interaction, and so on, are also affecting
the pharmacokinetics in drug absorption. These
factors will change the relationship between drug
intake and clinical response.
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