Pharmacokinetics

part 1
ABSORBTION

Pharmacokinetics - the action

of the body on the drug,
including absorption, distribution, biotransformation and
elimination.
Appropriate application
pharmacokinetic data and a few
simple formulas makes possible
the calculation of loading and
maintenance drug doses in the
treatment of certain diseases.

ABSORPTION OF DRUGS
To produce useful therapeutic effects, most drugs must be absorbed,
distributed, and eliminated.
Absorption - the process of a substance entering the blood
circulation.

Absorption is the transfer of a drug from its

site of administration to the bloodstream.
Most drugs are administered at a site distant from their target tissue. To reach
the target, they must permeate through both lipid and aqueous pathways.

Fig.10. [Mechanisms of drug permeation. Drugs may diffuse passively through

aqueous channels in the intercellular junctions (eg, tight junctions, A), or through
lipid cell membranes (B). Drugs with the appropriate characteristics may be
transported by carriers into or out of cells (C). Very impermeant drugs may also bind
to cell surface receptors (dark binding sites), be engulfed by the cell membrane
(endocytosis), and then released inside the cell or expelled via the membrane-limited
vesicles out of the cell into the extracellular space (exocytosis, D)].

Movement of drugs through the membrane occurs by means of:

aqueous diffusion;
lipid diffusion;
transport by special carriers;
transport by exocytosis and endocytosis (Fig.10).


Permeation
Drug permeation proceeds by several mechanisms. Passive diffusion in an
aqueous or lipid medium is common, but active processes play a role in the
movement of many drugs, especially those whose molecules are too large
to diffuse readily.
Aqueous

diffusion Aqueous diffusion occurs within the larger aqueous

compartments of the body (interstitial space, cytosol, etc) and across
epithelial membrane tight junctions and the endothelial lining of blood
vessels through aqueous pores thatin some tissuespermit the passage
of molecules as large as MW 20,00030,000.*

Aqueous

diffusion of drug molecules is usually driven by the concentration

gradient of the permeating drug, a downhill movement described by Ficks
law (see below). Drug molecules that are bound to large plasma proteins
(eg, albumin) do not permeate most vascular aqueous pores. If the drug is
charged, its flux is also influenced by electrical fields (eg, the membrane
potential andin parts of the nephronthe transtubular potential).

Lipid diffusionLipid diffusion is the most important limiting

factor for drug permeation because of the large number of lipid
barriers that separate the compartments of the body. Because
these lipid barriers separate aqueous compartments.

The capillaries of the brain, the testes, and some other tissues
are characterized by the absence of pores that permit aqueous
diffusion. They may also contain high concentrations of drug
export pumps. These tissues are therefore protected or
sanctuary sites from many circulating drugs.

lipid:aqueous partition coefficient of a drug determines how

readily the molecule moves between aqueous and lipid media. In
the case of weak acids and weak bases (which gain or lose
electrical charge-bearing protons, depending on the pH), the
ability to move from aqueous to lipid or vice versa varies with
the pH of the medium, because charged molecules attract water
molecules. The ratio of lipid-soluble form to water-soluble form
for a weak acid or weak base is expressed by the HendersonHasselbalch equation (described in the following text).

. Special carriersSpecial carrier molecules exist for many substances

that are important for cell function and too large or too insoluble in lipid
to diffuse passively through membranes, eg, peptides, amino acids, and
glucose. These carriers bring about movement by active transport or
facilitated diffusion and, unlike passive diffusion, are selective, saturable,
and inhibitable. Because many drugs are or resemble such naturally
occurring peptides, amino acids, or sugars, they can use these carriers to
cross membranes.

Many cells also contain less selective membrane carriers that are
specialized for expelling foreign molecules. One large family of such
transporters binds adenosine triphosphate (ATP) and is called the ABC
(ATP-binding cassette) family. This family includes the P-glycoprotein or
multidrug resistance type 1 (MDR1) transporter found in the brain,
testes, and other tissues, and in some drug-resistant neoplastic cells,

Similar transport molecules from the ABC family, the multidrug

resistance-associated protein (MRP) transporters, play important
roles in the excretion of some drugs or their metabolites into urine and
bile and in the resistance of some tumors to chemotherapeutic drugs.
Several other transporter families have been identified that do not bind
ATP but use ion gradients to drive transport. Some of these (the solute
carrier [SLC] family) are particularly important in the uptake of
neurotransmitters across nerve-ending membranes.

. Endocytosis and exocytosisA few substances are so

large or impermeant that they can enter cells only by
endocytosis, the process by which the substance is bound
at a cell-surface receptor,

engulfed by the cell membrane, and carried into the cell by

pinching off of the newly formed vesicle inside the membrane.
The substance can then be released inside the cytosol by
breakdown of the vesicle membrane, Figure 15D. This process is
responsible for the trans- port of vitamin B12, complexed with a
binding protein (intrinsic factor) across the wall of the gut into the
blood. Similarly, iron is transported into hemoglobin-synthesizing
red blood cell precursors in association with the protein
transferrin. Specific receptors for the transport proteins must be
present for this process to work.

The reverse process (exocytosis) is responsible for the secretion

of many substances from cells. For example, many
neurotransmit- ter substances are stored in membrane-bound
vesicles in nerve endings to protect them from metabolic
destruction in the cyto- plasm. Appropriate activation of the nerve
ending causes fusion of the storage vesicle with the cell
membrane and expulsion of its contents into the

extracellular space

Ficks Law of Diffusion

The passive flux of molecules down a concentration gradient is

given by Ficks law:

where C1 is the higher concentration, C2 is the lower

concentration, area is the cross-sectional area of the diffusion
path, permeability coefficient is a measure of the mobility of
the drug molecules in the medium of the diffusion path, and
thickness is the thickness (length) of the diffusion path. In the
case of lipid diffusion, the lipid:aqueous partition coefficient is
a major determinant of mobility of the drug, because it
determines how readily the drug enters the lipid membrane
from the aqueous medium.

Ionization

of Weak

Acids

and Weak

Bases;

The electrostatic charge of an ionized molecule attracts

water dipoles and results in a polar, relatively water-soluble
and lipid-in- lipid solubility, ionization of drugs may
markedly reduce their ability to permeate membranes. A
very large percentage of the drugs in use are weak acids or
weak bases (Table 13). For drugs, a weak acid is best
defined as a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a
proton (a hydrogen ion). For example, aspirin dissociates as
follows:soluble complex. Because lipid diffusion depends on
relatively high

A drug that is a weak base can be defined as a neutral

molecule that can form a cation (a positively charged molecule)
by combin-ing with a proton. For example, pyrimethamine, an
antimalarial drug, undergoes the following associationdissociation process:

 Factors

influencing absorption

Effect of pH on drug absorption:

Most drugs are either weak acids or weak bases.

Acidic drugs (HA) release a proton (H+), causing a
charged anion (A) to form:
HA H+ + A
Weak bases (BH+) can also release an H+.
However, the protonated form of basic drugs is
usually charged, and loss of a proton produces the
uncharged base (B):
BH+ B + H+

Note that the protonated form of a weak acid is the neutral,

more lipid-soluble form, whereas the unprotonated form of
a weak base is the neutral form. The law of mass action
requires that these reactions move to the left in an acid
environment (low pH, excess protons available) and to the
right in an alkaline environment. The HendersonHasselbalch equation relates the ratio of protonated to
unprotonated weak acid or weak base to the molecules
pKa and the pH of the medium as follows:

A drug passes through membranes more

readily if it is uncharged (Figure 1.7). Thus, for
a weak acid, the uncharged, protonated HA
can permeate through membranes, and A
cannot. For a weak base, the uncharged form,
B, penetrates through the cell membrane, but
BH+, the protonated form, does not.
Therefore, the eff ective concentration of the
permeable form of each drug at its absorption
site is determined by the relative
concentrations of the charged and uncharged
forms.

The ratio between the two forms is, in turn,

determined by the pH at the site of absorption and
by the strength of the weak acid or base, which is
represented by the ionization constant, pKa (Figure
1.8). [Note: The pKa is a measure of the strength of
the interaction of a compound with a proton. The
lower the pKa of a drug, the more acidic it is.
Conversely, the higher the pKa, the more basic is
the drug.]

Distribution equilibrium is achieved when the

permeable form of a drug achieves an equal
concentration in all body water spaces.
[Note:Highly lipid-soluble drugs rapidly cross
membranes and often enter tissues at a rate
determined by blood flow.]

Blood flow to the absorption site: Because

blood flow to the intestine is much greater than
the flow to the stomach, absorption from the
intestine is favored over that from the stomach.
[Note: Shock severely reduces blood flow to
cutaneous tissues, thereby minimizing the
absorption from SC administration.]

Total surface area available for

absorption: With a surface rich in brush
borders containing microvilli, the intestine has a
surface area about 1000-fold that of the
stomach, making absorption of the drug across
the intestine more efficient.

 Contact

time at the absorption surface:

If a drug moves through the GI tract very quickly, as

can happen with severe diarrhea, it is not well
absorbed. Conversely, anything that delays the
transport of the drug from the stomach to the
intestine delays the rate of absorption of the drug.
[Note: Parasympathetic input increases the rate of
gastric emptying, whereas sympathetic input
(prompted, for example, by exercise or stressful
emotions) as well as anticholinergics (for example,
dicyclomine), delays gastric emptying. Also, the
presence of food in the stomach both dilutes the drug
and slows gastric emptying. Therefore, a drug taken
with a meal is generally absorbed more slowly.]

Expression of P-glycoprotein: P-glycoprotein is a multidrug

transmembrane transporter protein responsible for transporting
various molecules, including drugs, across cell membranes
(Figure 1.9). It is expressed throughout the body, and its
functions include:

In the liver: transporting drugs into bile for elimination

In kidneys: pumping drugs into urine for excretion
In the placenta: transporting drugs back into maternal blood,
thereby reducing fetal exposure to drugs
In the intestines: transporting drugs into the intestinal lumen and
reducing drug absorption into the blood
In the brain capillaries: pumping drugs back into blood, limiting
drug access to the brain
Thus, in areas of high expression, P-glycoprotein reduces drug
absorption. In addition to transporting many drugs out of cells, it is
also associated with multidrug resistance .

Bioavailability
Bioavailability is the fraction of
administered drug that reaches the
systemic circulation.
For example, if 100 mg of a drug
are administered orally, and 70 mg
of this drug are absorbed
unchanged, the bioavailability is 0.7,
or 70 percent. Determining
bioavailability is important for
calculating drug dosages for nonintravenous routes of
administration.
The route by which a drug is
administered, as well as the
chemical and physical properties of
the agent, affects its bioavailability.

Determination of bioavailability: Bioavailability is

determined by

comparing plasma levels of a drug after a particular route of

administration
(for example, oral administration) with plasma drug levels
achieved by IV injection, in which the total agent rapidly enters
the circulation.
When the drug is given orally, only part of the administered dose
appears in the plasma. By plotting plasma concentrations of the
drug versus time, the area under the curve (AUC) can be
measured. This curve reflects the extent of absorption of the
drug.[Note: By definition, this is 100 percent for drugs delivered
intravenously.]
Bioavailability of a drug administered orally is the ratio of
the area calculated for oral administration compared with the
area calculated for IV injection if doses are equivalent (Figure
1.10).

Factors that infl uence bioavailability: In contrast to IV

administration, which confers 100% bioavailability, oral
administration of a drug often involves first-pass metabolism.
This biotransformation, in addition to the drugs chemical and
physical characteristics, determines the amount of the agent
that reaches the circulation and at what rate.

First-pass hepatic metabolism:

Solubility of the drug

Chemical instability

Nature of the drug formulation

First-pass hepatic metabolism: When a drug is absorbed

across

the GI tract, it first enters the portal circulation before entering

the systemic circulation (Figure 1.11). If the drug is rapidly
metabolized in the liver or gut wall during this initial passage,
the amount of unchanged drug that gains access to the systemic
circulation is decreased. [Note: First-pass metabolism by the
intestine or liver limits the efficacy of many drugs when taken
orally. For example, more than 90 percent of nitroglycerin is
cleared during a single passage through the liver, which is the
primary reason why this agent is administered via the sublingual
route]. Drugs that exhibit high first-pass metabolism should be
given in sufficient quantities to ensure that enough of the active
drug reaches the target concentration.

Solubility of the drug: Very hydrophilic drugs are poorly

absorbed because of their inability to cross the lipid-rich cell

membranes. Paradoxically, drugs that are extremely
hydrophobic
are also poorly absorbed, because they are totally insoluble
in aqueous body fluids and, therefore, cannot gain access to
the surface of cells. For a drug to be readily absorbed, it must
be largely hydrophobic, yet have some solubility in aqueous
solutions. This is one reason why many drugs are either weak
acids or weak bases.

Chemical instability: Some drugs, such as penicillin G,

are unstable in the pH of the gastric contents. Others,
such as insulin, are destroyed in the GI tract by
degradative enzymes.

Nature of the drug formulation: Drug absorption may

be altered by factors unrelated to the chemistry of the
drug. For example, particle size, salt form, crystal
polymorphism, enteric coatings, and the presence of
excipients (such as binders and dispersing agents) can
infl uence the ease of dissolution and, therefore, alter the
rate of absorption.

This equation applies to both acidic and basic drugs.

Inspection confirms that the lower the pH relative to the
pKa, the greater will be the fraction of drug in the
protonated form. Because the uncharged form is the more
lipid-soluble, more of a weak acid will be in the lipid-soluble
form at acid pH, whereas more of a basic drug will be in the
lipid-soluble form at alkaline pH.

ABSORPTION OF DRUGS

Absorption is the transfer of a drug from its site of

administration to the bloodstream via one of several
mechanisms. The rate and effi ciency of absorption depend on
both factors in the environment where the drug is absorbed
and the drugs chemical characteristics and route of
administration (which infl uence its bioavailability). For IV
delivery, absorption is complete. That is, the total dose of
drug administered reaches the systemic circulation (100%
bioavailability). Drug delivery by other routes may result in
only partial absorption and, thus, lower bioavailability.

Bioequivalence:

Two related drug preparations are bioequivalent if they show

comparable bioavailability and similar times to achieve peak
blood concentrations.

Therapeutic equivalence

Two similar drug products are therapeutically equal if they are

pharmaceutically equivalent with similar clinical and safety
profiles. [Note: Clinical effectiveness often depends on both the
maximum serum drug concentrations and on the time required
(after administration) to reach peak concentration. Therefore,
two drugs that are bioequivalent may not be therapeutically
equivalent.]

Mechanisms of absorption of drugs from the GI tract

Depending on their chemical properties, drugs may be

absorbed from the GI tract by passive diff usion, facilitated diff
usion, active transport, or endocytosis.

1. Passive diffusion: The driving force for passive absorption

of a drug is the concentration gradient across a membrane
separating two body compartments. In other words, the drug
moves from a region of high concentration to one of lower
concentration. Passive diffusion does not involve a carrier, is
not saturable, and shows a low structural specifi city. The vast
majority of drugs gain access to the body by this mechanism.
Water-soluble drugs penetrate the cell membrane through
aqueous channels or pores, whereas lipid-soluble drugs readily
move across most biologic membranes due to their solubility in
the membrane lipid bilayers (Figure 1.6A).

 Facilitated

diffusion:

Other agents can enter the cell through

specialized transmembrane carrier proteins that
facilitate the passage of large molecules. These
carrier proteins undergo conformational
changes, allowing the passage of drugs or
endogenous molecules into the interior of cells
and moving them from an area of high
concentration to an area of low concentration.
This process is known as facilitated diff usion. It
does not require energy, can be saturated, and
may be inhibited by compounds that compete
for the carrier (Figure 1.6B)

Active transport:
This mode of drug entry also involves specific carrier proteins
that span the membrane. A few drugs that closely resemble the
structure of naturally occurring metabolites are actively
transported across cell membranes using these specifi c carrier
proteins. Energy-dependent active transport is driven by the
hydrolysis of adenosine triphosphate (Figure 1.6C). It is capable
of
moving drugs against a concentration gradient, from a region
of low drug concentration to one of higher drug concentration.
The process shows saturation kinetics for the carrier, much in
the same way that an enzyme-catalyzed reaction shows a
maximal velocity at high substrate levels where all the active
sites are fi lled with substrate.
Active transport systems are selective and may be
competitively inhibited by other cotransported substances.

Endocytosis and exocytosis:

These types of drug delivery systems transport drugs

of exceptionally large size across the cell membrane.
Endocytosis involves engulfment of a drug molecule by
the cell membrane and transport into the cell by
pinching off the drugfi
lled vesicle (Figure 1.6D). Exocytosis is the reverse of
endocytosis
and is used by cells to secrete many substances by a
similar vesicle formation process. Vitamin B12 is
transported across the gut wall by endocytosis,
whereas certain neurotransmitters (for example,
norepinephrine) are stored in intracellular membranebound vesicles in the nerve terminal and are released
by exocytosis.

DRUG DISTRIBUTION

After absorption, drugs are distributed to

different parts of the body. Drug distribution is
the process by which a drug reversibly leaves
the bloodstream and enters the interstitium
(extracellular fluid) and then the cells of the
tissues.
So, distribution may be restricted to the
extracellular space (plasma volume plus interstitial
space) or may also extend into the intracellular space.
Certain drugs may bind strongly to tissue structures
so that plasma concentrations fall significantly even
before elimination has begun. So, in this case drug
concentration is higher in tissues than in the
extracellular fluids and blood.

Lung and skin

Furthermore,
drug
absorption is faster from
organs with thin membrane
barriers (eg, the lung) than
from
those
with
thick
barriers (example, the skin).

Rate of absorption depends on:

Routes of administration;

Blood flow in the tissues;

Concentration of drug.

Drug absorption is
faster from organs
with large surface
areas, such as the
small intestine, than
from
organs
with
smaller
absorbing
areas (the stomach).

Small intestine and stomach

Have a nice day!

If you have any questions write me an e-mail:

nato.alavidze@atsu.edu.ge
Contact information: 5 99 516022