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.