FOOD, GASTROINTESTINAL PH, AND MODELS OF ORAL DRUG ADSORPTION.

Oral dosing of drug à most common route of adminsitratrion, it Is a complex process affected by numerous
factors associated with:

- The drug’s physicochemical properties,

- The nature of the dose administration, and
- The gastrointestinal physiology.

Factors that affect GI tract:

- GI pH.
- GI transit time.
- Presence of food
- Other factors such as age and GI/systemic diseases.

Food-drug interactions may result in one of four possible out- comes:

- delayed absorption,
- decreased absorption,
- increased absorption, and
- sometimes, unaffected drug absorption

2. THE BIOPHARMACEUTICAL CLASSIFICATION SCHEME.

CLASS SOLUBILITY PERMEABILITY ORAL ABSORPTION

I HIGH HIGH Generally very well-absorbed
II LOW HIGH Exhibit dissolution rate-limited absorption
III HIGH LOW Exhibit permeability rate-limited absorption
IV LOW LOW Exhibit limited absorption and very poor oral
bioavailability

3. HUMAN GASTROINTESTINAL pH.

3.1. Gastrointestinal pH in different population subgroups

Patients with upper GI diseases may show different gastric acid- ity compared to healthy individuals

3.2. Effect of GI pH variability on oral drug absorption and bioavailability.

Alterations in GI pH may influence drug dissolution and solubility, drug release, drug stability and intestinal
permeability.

Variability in GI pH is among the factors that can impact oral drug absorption and bioavailability.

Drug dissolution and solubility.

Weakly basic drugs à dissolve more readily in the acidic environment of the stomach but as they move
towards a more basic environment, their solubility is reduced which may result in drug precipitation.

Weakly acid drugs à the dissolution is minimal in the stomach and the solubility tends to increase as the
drug passes to the more basic environment of the small intestine.
An elevation of gastric pH is expected to diminish the in vivo dissolution and absorption of weakly basic drugs
but enhance the in vivo dissolution and absorption of weakly acidic drugs.

The effect of gasctric pH on the in vivo drug is most pronounced with weakly basic poorly water-soluble,
highly permeable drugs (BCS Class II).

Elevated gastric pH diminish the dissolution of poorly-water soluble weakly basic drugs, however, when the
drug is lipophilic, this effect may be offset by bile-mediated solubilization and/or increases gastric residence
time.

Drug release (liberación de medicamento).

Drug release from coated formulations may be influenced by GI pH.

Enteric coated dosage forms are designed to protect gastric mucosa from possible irritation caused by the
drug or to protect acid-labile drugs from degradation in the gastric fluid.

Variability in GI pH may affect drug release.

Intestinal permeability.

Most drugs are absorbed from the GI tract through passive dif- fusion across the intestinal membrane

According to the pH-partition hypothesis, biological membranes are predominately lipophilic and favour the
transport of drugs in their molecular (un-ionized) forms. Therefore, an increase in the fraction of the un-
ionized form of the drug will most likely result in an increased permeability through the intestinal membrane.

Changes in the pH of the GI tract (e.g. after a meal) are expected to mainly affect the absorption rate as a
consequence of affecting the percentage of the un-ionized drug at the absorption site.

Drug stability.

Drug stability in the GI tract is an important factor when considering oral bioavailability. Acid-labile drugs are
susceptible to degradation in the acidic pH of gastric contents.

An increase or a decrease in gastric pH for acid-labile drugs is expected to result in an enhanced or decreased
oral bioavailability, respectively.

4. GASTROINTESTINAL TRANSIT TIME (GITT).

GITT is determined by the GI motility patterns, which differs between fasted and fed states with high
between and within sub- ject variability

In the fasted state, GI transit is mainly regulated by the migrating myoelectric complex (MMC).

The MMC is an organized recurring motility cycle that originates from the stomach and propagates along the
small intestine and is initiated by cyclic electromechanical activity in the smooth muscles of the GI tract. The
MMC occurs only during inter-digestive periods to clear the indigestible food remnants from the stomach
and small intestine to the colon.

1. Basal phase (Phase I) is a quiescent period with no gastric secretions or contractions and lasts for
about 40–60 min.
 2. The pre-burst phase (Phase II) lasts for 40–60 min and is characterized by progressive increase in
contraction intensity and frequency.
3. The frequency and intensity of the contractions peak for a short time (4 min to 6 min) in the burst
phase (Phase III) resulting in clearance of the undigested solids from the stomach to the small
intestine and cecum and, hence, is termed the ‘‘housekeeping wave”
4. The last phase (Phase IV) is a transition phase of 0 min to 5 min between Phase III and Phase I.

5. EFFECT OF FOOD ON ORAL DRUG ABSOPTION AND BIOAVAILABILITY.

Food exerts its effects on oral absorption through direct and indirect ways:

- Indirect effects: occur as a result of aletering the GI physiology.

- Direct effects: such as in the case of binding the drug with food components.

Food-drug interactions are highly complex and can be further affected by the type of ingested food as well
as the nature of the administered formulation.

Delayed or slower drug absoption.

The rate of drug absorption is decreased while the extent of absorption is not significantly changed.

Usually occurs with high solubility, high permeability (BCS Class I) and rapidly absorbed drugs

The main mechanism responsible for the delayed absorption, when the drug is administered with food, is
the decrease in the rate of gastric emptying.

Decreased drug absoption.

The extent of absorption is markedly decreased with a corresponding reduction in Cmax

The mechanisms behind reduced absorption with food can be due to the instability of the drug in gastric
fluids, physical or chemical binding of the drug with food components, elevation of the viscosity of GI fluids,
and enhanced first-pass metabolism.

- Instability of the drug in gastric fluids. Drugs that are unstable in gastric fluids will exhibit reduced
bioavailability when administered with food as a result of their increased residence time in stomach.
- Drug binding with food components. The presence of bile acids can have dual effects on drug absorp-
tion. On one hand, the tight complexation between hydrophilic drug molecules and bile acids can
lead to a considerable decease in GI absorption and bioavailability
- Elevated viscosity of the GI fluid. inverse relationship between increased gastric viscosity, after
ingestion of food, and drug absorption.

The postprandial increase in viscosity may serve as a physical barrier to drug release from the
adminis- tered solid dosage forms and may hinder the diffusion of the dis- solved drug to mucosal
surface, and therefore, reducing the extent of drug absorption [91,92]. The effect of viscosity on the
drug release is particularly important for oral formulations con- taining BCS Class III drugs (high
solubility/low permeability).

Although it is true that ingestion of food increases gastric vis- cosity, the viscosity is reduced
progressively over time due to rapid dilution by the salivary and gastric acid secretions in response
to the food.
 - Enhanced pre-systemic (first-pass) metabolism. this effect is usually small in magnitude but may be
of importance with lipophilic drugs that have a narrow therapeutic window.

Increased pre-systemic metabolism might be a result of reduced rate of drug absorption in the
presence of food, leading to higher percentage of the absorbed drug being susceptible for
metabolising enzymes.

Increased drug absorption.

increased oral absorption is manifested by a significant increase in the AUC with a correspond- ing increase
in the Cmax of absorbed drugs. Increased absorption is commonly seen with poorly water-soluble drugs
when co- administered with food; especially, fatty meals.

- Enhanced drug solubilization and dissolution. Ingestion of food delays gastric emptying and
enhances pancre- atic and bile acid secretion into the duodenum. The delayed gas- tric emptying
(i.e. increase gastric residence time) of drug particles can enhance the dissolution of drugs that show
a higher solubility at gastric pH values.

The increased concentra- tion of bile acids in the duodenum enhances the dissolution of lipo- philic
drugs and, hence, improves partitioning of the drugs into the intestinal membrane.

- Decreased pre-systemic drug metabolism. Pre-systemic drug metabolism can be reduced indirectly.
The administration of food is associated with an increase in splanchnic blood flow and an increase in
the transport of drugs through the lymphatic system which can both decrease pre-systemic metabo-
lism.

Unaffected drug absoption.

Drugs in this category show minimal or no change in the rate and extent of absorption between fasting and
fed state. Drugs in this category include:

a. Drugs that are not influenced by the food-induced physiological changes in the GI tract.
b. Drugs that are com- pletely and rapidly absorbed from the GI tract.
c. Drugs that have site-independent absorption and can be readily absorbed from the different regions
of the GI tract.

Food interactions with the formulation.

The influence of food on drug absorption is affected by:

- the nature of the dosage form,

- the excipients used in the formulation, and
- the particle size of the formulated drug.

The food-induced physiological changes can interfere with the formulation components and drug release,
thus, affecting absorption and bioavailability

Formulation excipients can further complicate the effects of food on absorption

In vitro dissolution methods that adequately mimic the normal gastrointestinal environment after food
intake have been used to explore food-drug and/or food-formulation interactions in order to better predict
the in vivo drug dissolution and absorption of orally administered drugs
6. MODELS OF ORAL DRUG ABSORPTION.

EMPIRICAL ABSORPTION MODELS.

TYPICAL EMPIRICAL ABSORPTION MODELS.

Generally assume zero-order or first-order
absorption kinetics, with or without a lag time,
where the absorption rate constants can be easily
obtained by simple compartmental modelling of
the drug’s plasma concentration-time profile.

ATYPICAL EMPIRICAL ABSORPTION MODELS. They

are more flexible than typical empirical absorption
models.

- Two parallel first-order absoption.

- Mixed first- and zero-order absoption.
- Weibull-type absorption: applied to
describe more complex profiles when the
zero-order, first-order, or mixed-order absoption models cannot satifacterily characterize the
process.
- Inverse Gussian density absorption.
- Time-dependent absorption rate constante.
- Michaelis-Menten absorption window: to describe saturable transport-mediated absorption with an
absorption window.
- Transit compartment model.

PHYSIOLOGICALLY-BASED ABSORPTION MODELS.

The basis of the mechanistic absorption models is the prior information on both the drug which are obtained
from in vitro experiments or based on the drug’s chemical structure, and physiology.

DISPERSION MODEL. Used to simulate time-dependent absorption from the GI tract. It considerts the GI
tract as a one-dimensional cylindrical tube with spatially different properties.

It predicted the fraction absorbed of many passively absorbed drugs.

COMPARTMENTAL ABSORPTION AND TRANSIT (CAT) MODEL. Drug passage through the small intestine was
described as flow through a series of seven transit compartments where each represented a segment of the
small intestine.

The compartments act as delay ele- ments and may have different volumes and flow rates but all have the
same transit rate constant (Kt).

The original CAT model assumed instantaneous dissolution, passive absorption, linear transfer kinetics from
each GI segment, negligible pre-systemic metabolism and minor absorption from the stomach and colon.

ADVANCED CAT (ACAT) MODEL. The model consisted of nine compartments representing stomach, the
seven CAT model compartments, and the colon.

The ACAT model distinguished between six states of drug substance: unreleased, undissolved, dissolved,
degraded, metabolized, and absorbed drug substance.
The ACAT model takes into account the physicochemical, physiological, and dosage form factors in predicting
oral drug absorption.

ADVANCED DISSOLUTION, ABSORPTION AND METAMOLISM (ADAM) MODEL. Structured based on the CAT
model

OTHER MODELS: GRASS MODEL AND GI TRANSIT AND ABSORPTION (GITA) MODEL.

- GRASS MODEL: predicts the absoption form the GI compartments based on solubility and
permeability of the drug, and tissue surface area. It has several limitations as it does not account for
drug degradation, first-pass metabolism, and active transport processes.
- GITA MODEL: predicts oral absoption in rats, divided the GI tract into 8 comparments with each
compartment having different transit and absoption kinetics.

SIMPLIFIED POPULATION-BASED ABSORPTION MODELS.

While whole-body PBPK models often have high physiological and pharmaceutical fidelity, they are highly
complex and multi- dimensional compared to classical models.

Whole-body PBPK models generally do not typically represent between subject variability or are too slow to
solve for modelling of large data sets.
BIOSIMILAR DRUGS
1. OVERVIEW OF BIOSIMILARS IN PHARMACEUTICAL REGULATION.

Guidelines à regulatory processes.

The FDA has already stated that more data will be required to prove the efficacy and safety of generic
versions of more complex protein-based biotechnology drugs than are re- quired for simpler compounds.
They acknowledge that the amount of data required will partly be a function of the complexity of the
compound and how well it can be characterized.

2. DIFFERENCES BETWEEN BIOPHARMACEUTICALS AND TRADITIONAL DRUGS.

Feature TRADITIONAL PHARMACEUTICALS BIOPHARMACEUTICALS

The chemical identity of such agents can be confirmed by exact analytical techniques such
as spectrometry and nuclear magnetic resonance. These techniques can also enable con-
taminants and impurities to be detected, such as reactive inter- mediates or degradation
products.
Synthesis Product quality determined largely by Tool-driven (e.g. expression vectors and cell
experience of the operator and replicable lines), resulting in variable final product
in different laboratories between laboratories
Purification Often based on standardized procedures Desired product is very poorly represented
composed of a few steps. Also, facilitated in the mixture. Also, contaminants are
by final product often being the principal qualitatively preponderant and probably
component of the reaction, and when it is vary among laboratories
not, other product components are
qualitatively limited and known
Stability Usually degrade with first-order kinetics, Unlikely that the principles applying to
which can normally be modeled using the degradation of traditional pharmaceuticals
Arrhenius equation can also be applied to biopharmaceuticals,
due to their size, complexity of tertiary
structure, and post- translational
modifications
Immunogenic Reactions to active ingredient or excipients Reactions to biotechnology products may be
reactions are intrinsic to the patient and, therefore, attributable to both product- and host-
not easily attributable to a specific related factors.
pharmaceutical product

3. CONSIDERATIONS FOR BIOSILIMILAR REGULATORY GUIDELINES.

‘Biosimilar’ cannot be a synonym for ‘generic.’

Original product and the biosimilar drug cannot be considered equal. Legislative procedures that are in
force for generic drugs cannot be applied to biosimilar drugs.

A biosimilar drug will require considerably less preregistration studies compared with the original product,
but more than those presently required for the introduction of a traditional generic drug.

1. Before entering clinical investigation, a biosimilar should be characterized in preclinical studies. A

toxicity study with repeated dose administration should be conducted, including toxicokinec dosages,
but that other routine toxicology studies should not be necessary, unless other are reasons to
consider them necessary.
 2. A comparative phase I trial with the original product is essential to evaluate similarity of
pharmacokinetic parameters.
3. A phase III comparative study should be performed to evaluate the therapeutic efficacy of the
biosimilar. The clinical trial should be sufficiently powered to reveal possible adverse effects,
particularly immunogenicity and toxicity. In the case of more than one therapeutic indication, it
would be sufficient to demonstrate efficacy of the biosimilar for a single indication and extrapolate
such efficacy for other indications.

As a biosimilar is not comparable with a generic drug, it is essential that a patient’s pharmacologic history
takes into account which biopharmaceuticals they have received. The name of the active principle is
insufficient since this may refer to the original biopharmaceutical product or to one of many biosimilars.

It is therefore necessary that individual biosimilars, includ- ing those of the same original biopharmaceutical,
be clearly recog- nizable, but at the same time it should be clear that they are part of the appropriate
therapeutic class

4. FACTOR AFFECTING THE INTRODUCTION OF BIOSIMILARS INTO CLINCAL PRACTICE.

1. Which patients can be immediately considered candidates for treatment with biosimilars without
reserve, and which require greater attention?

Each patient will have their own particular history. It could be suggested that newly diagnosed patients who
are ‘biodrug-naive’ will not pose particular problems in terms of the rapid adoption of biosimilars.

Utmost caution would be warranted when changing therapeutic compounds in patients with a complex
clinical history in terms of achieving therapeutic res- ponse, perhaps after repeated attempts with various
original drugs

2. Who should decide on substituting the original ‘drug’ with a biosimilar and on what grounds should
‘automatic drug substitution’ be implemented?

Substitution without the previous approval of the clinician is not advisable, at least during the first years of
market- ing. Such prohibition will allow each single patient’s therapeutic route to be tracked with greater
certainty, and possibly develop the necessary links between pharmacovigilance ‘findings’ and effec- tive
exposure of patients to individual products

The prohibition of automatic substitution for biosimilars has already been introduced in some countries

3. To what extent can the substitution of one biosimilar for another be repeated over time and with what
repercussions?

The considerations argued above should discourage indiscriminate repeated substitution of similar biotech-
nology products, even in the presence of medical supervision. Repetitive ‘switching’ between such agents
should be considered an additional risk.
IN VITRO-IN VIVO CORRELATION: IMPORTANCE OF DISSOLUTION IN IVIVC.
Correlations between in vitro and in vivo data (IVIVC) are often used during pharmaceutical development in
order to reduce development time and optimize the formulation.

IVIVC à a predictive mathematical model describing the relationship between an in vitro property of an
extended release dosage form (usually the rate or extent of drug dissolution or release) and a relevant in
vivo response.

Bases on the type of data used to establish the relationship, three

main levels are defined by the FDA:

- LEVEL A: A correlation of this type is generally linear and

represents a point-to-point relationship between in vitro
dissolution and the in vivo input rate. Level A correlations use
all the information of the dissolution and absoption curves, in
contrast to levels B or C.
- LEVEL B: uses the principles of statistical moment analysis.
- LEVEL C: establishes a single point relationship between a dissolution parameter and a
pharmacokinetic parameter.

In addition to these three levels, a combination of various levels C is also described: A multiple Level C
correlation relates one or several pharmacokinetic parameters of interest to the amount of drug dissolved
at several time points of the dissolution profile.

A Level A IVIVC is considered the most informative and is recommended, if possible. Multiple Level C
correlations can be as useful as Level A correlations. However, if a multiple Level C correlation is possible,
then a Level A correlation is also likely and is preferred. Level C correlations can be useful in the early stages
of formulation development when pilot formulations are being selected. Level B correlations are least useful
for regulatory purposes.

DATA COLLECTION.

IN VIVO DATA.

The in vivo data are derived from the plasma concentration curve.

The plasma concentration curve is a global representa- tion; it depends on drug input within the blood, which
depends on the dosage form and the properties of the drug, and thereafter its pharmacokinetic input
processes.

IN VITRO DATA.

INTEREST OF IN VITRO DISSOLUTION.

In the case of oral administration of a solid dosage form, the limiting factor for the appearance of the drug
in the blood could be the pure permeability through the intesti- nal membrane

In case of solubility-limited product, the absorption could be governed by physico-chemical characteristics

of the API and not by its permeability or formulation
Correlations are always possible with Class I drugs and depend on the relative magnitude of the various
factors versus the release rate for the other classes. The active substance is the core of any formulation; the
physico-chemical characteristics and the stability of the API are the main points to be considered first.

In the case of oral products, there are two types of formulations:

- Immediate-release (IR) formulation: the relase of both the drug and excipients is rapid. The excipients
are usually materials without biopharmaceutical properties and do not dramaticall modify the
release of the drug even if present in large quantity.
- Extended-release (ER) formulation: the excipients are the core of the formulation, and they control
de release of drug within the body.

IN VITRO DATA.

Various dissolution tests exist and can be used to gener- ate the in vitro data. In order to compare the results,
the same method must be used for all the formulations.

The best dissolution method for in vivo—in vitro correla- tion is, obviously, the method that describes what
happens in vivo. The main factors that can influence drug release in vivo are presented in Figure 3. All of
these factors cannot be easily reproduced in vitro by a simple dissolution method.

IN VITRO MEDIA.

For specific applications (e.g., poorly soluble drugs), the pharmacopeias recommend the addition of either
enzymes or surfactant.

IN VITRO APPARATUS.

not all the factors described in Figure 3 can be reproduced in vitro even if some attempts exist. Any
compendial method that can discriminate between the formulations may be used, but certain techniques
are preferred.

In vitro system developed to date can maintain the following requirements that correspond to the
physiological states in vivo:

1. sequential use of enzymes in physiological amounts,

2. appropriate pH for the enzymes,
3. removal of the products of digestion,
4. appropriate mix- ing at each stage of digestion,
5. physiological transit times for each step of digestion, and,
6. a peristaltic dynamic approach.
TNO Gastro-Intestinal Model: is an in vitro system developed at TNO Nutrition and Food Research that
simulates the GI tract in man and fulfills the requirements mentioned above. This in vitro model offers the
possibility of introducing a solid meal to investigate all food–drug interactions and food impact on dosage
form behaviour. It consists of four serial compartments simulating the stomach and the three segments of
the small intestine: the duodenum, jejunum, and ileum

Although this Artificial Digestive System has been widely used in nutrition studies, few examples of drug
dosage forms have been studied. However, this type of system, even if it could be used in drug development
with success (19, 22, 23), is not a quality control tool due to its complexity.

The classical methods do not allow all the characteristics of the in vivo interaction to be reproduced but can
help to study the mean characteristic of drug release.

SIGNIFICANCE OF LEVEL A CORRELATION.

A Level A correlation defines a linear relationship between in vitro and in vivo data so that measurement of
the in vitro dissolution rate alone is sufficient to determine the pharmacokinetic profile in vivo.

In vitro dissolution testing is important for:

1. providing process control and quality assurance,

2. determining stable release characteristics of the product over time; and
3. facilitating certain regulatory determinations

In certain cases, especially for ER formulations, the dissolu- tion test can serve not only as a quality control
for the manufacturing process but also as an indica- tor of how the formulation will perform in vivo. Thus, a
main objective of developing and evaluat- ing an IVIVC is to establish the dissolution test as a surrogate for
human bioequivalence studies....

CONCLUSION.

Level A IVIVCs define the relationship between an in vitro dissolution curve and an in vivo input (absorption)
profile. A Level A correlation should always be tried a priori in order to have a tool that allows a complete in
vivo predic- tion from an in vitro dissolution curve and thus accelerates the development and assists in some
regulatory aspects (SUPAC). The correlation quality depends solely on the quality of the data. As in vivo data
are now well standard- ized, the main effort must be directed to the in vitro data. Various apparatus and
media should be tested and assessed in terms of their in vivo predictability. The user should always be aware
of the limits of the method and of the confidence of its prediction.
FACTORS AFFECTING DRUG ABSORPTION AND DISTRIBUTION.
A drug is a chemical that affects physiological function in a specific way, generally by binding to particular
target proteins. The action of a drug requires the presencie of an adquete concentration of the drug in the
fluid.

PASSAGE OF DRUGS ACROSS CELL MEMBRANES.

The passage of drugs across cell membranes is necessary for most pharmacokinetic processes.

Drugs are transported around the body in two ways:

- By bulk flow (i.e. in the bloodstream).

- By diffusional transfer, predominantly across cell membranes.

Mechanisms of Passage of drugs across cell membranes:

- Passive diffusion: is the passive movement of a substance from an area of high concentration to an
area of lower concentration. The rate of diffusion is determined by:
o Molecular size: rate of passive diffusion is inversely proportional to the square root of
molecular size.
o Concentratation gradient: the rate of diffusion across a membrane is proportional to the
concentration gradient across the membrane.
o Lipid solubility: non-polar substances dissolve freely in lipids and therefore easily diffuse
through cell membranes.
o Degree of ionization of the drug: only the un-ionized fraction of a drug is available to cross
the cell membrane because of the lipid nature of the membrane. The degree of ionization of
a drug in solution depends on the molecular structure of the drug and the pH of the solution.
o Protein binding: only free unbound drug is available to cross the cell membrane.
- Filtration: aqueous channels in the tigh juntions between adjacent epithelial cells allow passage of
some water-soluble substances. Non-polar molecules pass most readily as the channels are
electrically charged.
- Carrier-mediated transport: this is the mechanism used by drugs to cross cell membranes against a
concentration gradient. The drugs that are subject to these processes are structurally similar to
natural constituents of the body. The carriers involved are subject to saturation and can be inhibited.
- Pinocytosis involves invagination of part of the cell membrane around a drug molecule, thus
incorporating it into the cell within a small vacuole.

DRUG ABSORPTION.

Absorption is the passage of a drug from its site of administration into the plasma. Intravenous
administration, therefore, requires no absorption.

In some instances, administration is directly to the effect site, and therefore absorption into the plasma is
not required for the therapeutic effect of the drug. In such cases, ab- sorption gives rise to the unwanted
side effects of the drugs.

Many different routes may be used to administer drugs:

- Injections (intravenous, intramuscular, subcutaneous or intrathecal).

o Intravenous injection: is the most direct route of administration, providing a patient with
drug that is immediately available for distribution to its effect sites.
 Absorption from the site of injection can be increased by the application of heat or massage, both of
which increase local blood flow.
Oral administration: is the most common route of drug administration. The low pH of the stomach
means that acidic drugs are largely un-ionized. However, the small surface area and relatively rapid
gastric emptying means that the stomach does not have a significant role in absorbing drugs.
The principal site of absorption of orally administered drugs is the small intestine
Bioavailability: the proportion of a drug that en- ters the systemic circulation compared with the
same dose given intravenously.
Oral bioavailability depends not only upon the ability of a drug to penetrate the gut mucosa, but also
upon the extent to which the drug is metabolized either by enzymes in the gut wall or in the liver.
Other factors affect oral bioavailability:
o drug formulation (particle size, tablet size, enteric coating and pressure used in the tabletting
machine can affect drug dispersion);
o physicochemical interactions with other drugs or food leading to binding of the drug and
reduced absorption; and
o various patient factors such as malabsorption syndromes or altered intestinal mobility. In
addition, concentration of drug entering the intestine and gastrointestinal transit times
affects the degree of saturation of intestinal enzymes and hence the extent of first-pass
metabolism.
- Rectal. The rectal route may avoid first-pass metabolism and is useful for drugs that would otherwise
be inactivated rapidly in the liver.
- Sublingueal. The oral mucosa has a rich blood supply that bypasses the portal circulation. Therefore,
the sublingual and buccal routes are useful when a rapid effect is required, particularly for drugs that
are unstable at gastric pH or rapidly metabolized by the liver.
- Topical administration. Although topical drugs are often given for their local effects, certain highly
lipid-soluble drugs may be given transdermally for systemic ef- fects. This route avoids first-pass
metabolism and can provide a steady rate of drug delivery over a few days
- Inhalational. Inhaled drugs can be given for either local or systemic effects. Systemic ab- sorption
occurs when particles reach the alveoli, and this is dependent on particle size.

DISTRIBUTION OF DRUGS IN THE BODY.

Once drugs have been absorbed into the circulation, they need to be distributed to their effect sites to exert
their clinical effects

Distribution to individual tissues depends on blood flow to the tissues, and solubility and uptake into those
tissues.

BODY FLUID COMPARTMENTS.

Body water compartments drug molecules will exist in both free solution and bound form and in an
equilibrium mixture of charged and un-charged forms.

VOLUME OF DISTRIBUTION AND COMPARTMENT MODELS.

Volume of distribution: volume of fluid required to contain the total amount of drug in the body at the same
concentration as that present in the plasma.

Single-compartment model: the plasma and all tissues are considered as one compartment, throughout
which the drug is evenly distributed and from which it is eliminated in an exponential. However, the single-
compartment model is too simple to describe drug behaviour and so multicompartment models are used.
Multicompartment models may include any number of
theoretical compartments, but more than three become
experimentally indistinguishable.

In the two-compartment model, the tissues are considered

together as the peripheral compartment that drug molecules can
enter and leave only via the central compartment, which is
generally considered to be the plasma. Adding a second
compartment introduces a second exponential component into
the predicted time course of the change in plasma concentration.
The first ‘fast’ process represents distribution and the second
‘slow’ process represents terminal elimination, which comprises
both elimination from the body and redistribution of drug to
plasma from the second compartment.

DISTRIBUTION OF DRUGS TO THE FETUS.

The rate of equilibration of drugs across the placenta is determined by placental blood flow and the free
drug concen- tration gradient across the placenta. The pH of fetal blood is lower than that of the mother
and this may affect drug transfer across the placenta in two ways. The degree of ionization of drugs is
altered in fetal blood.

the pH differences in maternal and fetal blood alter the relative protein binding of drugs across the
placenta, which in turn alters the free drug concentration gradient across the placenta. Higher protein
binding in the fetus would increase drug transfer from mother to fetus, whereas higher protein binding in
the mother would reduce drug transfer from mother to fetus.