Prodrugs

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GASTROINTESTINAL PHYSIOLOGY
• Drugs, via drug delivery systems, are most often
administered to human subjects by the oral route.
Compared to other routes of drug administration,
especially the intravenous route, the oral route is
unusually
complex
with
respect
to
the
physicochemical conditions existing at the
absorption site. Therefore, before we discuss how
the biopharmaceutical properties of a drug in a
dosage form can affect the availability and action of
that drug, it is prudent to review gastrointestinal
physiology.
Processes occurring along with drug absorption when drug molecules travel
down the gastrointestinal tract and the factors that affect drug absorption.
Biologic Membrane
• The prevalent view of the gastrointestinal membrane is that it
consists of a bimolecular lipoid layer covered on each side by
protein, with the lipid molecule oriented perpendicular to the cell
surface. The lipid layer is interrupted by small, water-filled pores with
a radius of approximately 4 Å. A molecule with a radius of 4 Å or less
can easily pass through these water-filled pores. Thus, membranes
have a specialized transport system to assist the passage of watersoluble material and ions through the lipid interior, a process
sometimes termed “convective absorption.”
• When permeation through the membrane occurs, the permeating
substance is considered to have transferred from solution in the
luminal aqueous phase to the lipid membrane phase, then to the
aqueous phase on the other side of the membrane.
• Biologic membranes differ from a polymeric membrane in that they
are composed of small amphipathic molecules, phospholipids, and
cholesterol. The protein layer associated with membranes is
hydrophobic in nature. Therefore, biologic membranes have a
hydrophilic exterior and a hydrophobic interior.
Biologic Membrane
• Cholesterol is a major component of most mammalian biologic
membranes, and its removal renders the membrane highly
permeable. Cholesterol complexes with phospholipids, and its
presence reduces the permeability of the membrane to water,
cations, glycerides, and glucose.
• In addition to biopharmaceutical factors, several physiologic factors
can also affect the rate and extent of gastrointestinal absorption.
These factors are as follows: properties of epithelial cells, segmental
activity of the bowel, degree of vascularity, effective absorbing
surface area per unit length of gut, surface and interfacial tensions,
electrolyte content and their concentration in luminal fluid, enzymatic
activity in the luminal contents, and gastric emptying rate of the drug
from stomach.
Sequence of events in drug absorption from formulations of
solid dosage forms.
Basic structure of an animal cell membrane.
Mechanisms of Drug Absorption
1) Passive Diffusion
•
•
The transfer of most drugs across a biologic
membrane occurs by passive diffusion, a
natural tendency for molecules to move from a
higher concentration to a lower concentration.
This movement of drug molecules is caused
by the kinetic energy of the molecules. The
rate of diffusion depends on the magnitude of
the concentration gradient across the
membrane.
The greater the concentration of drug at the
absorption site, the faster is the rate of
absorption.
Mechanisms of Drug Absorption
1) Passive Diffusion
•
A major source of variation is
membrane permeability, which
depends on the lipophilicity of the
drug molecule. This is often
characterized by its partition
between oil and water. The lipid
solubility of a drug, therefore, is a
very important physicochemical
property governing the rate of
transfer through a variety of
biologic membrane barriers.
Mechanisms of Drug Absorption
1) Carrier-Mediated or Active Transport
• Although most drugs are absorbed from the gastrointestinal tract by
passive diffusion, some drugs of therapeutic interest and some
chemicals of nutritional value, such as amino acids, dipeptides and
tripeptides, glucose, and folic acid, are absorbed by the action of
transporter proteins (i.e., a carrier-mediated transport mechanism).
• The usual requirement for active transport is structural similarities
between the drug and the substrate normally transported across the
membrane. Active transport differs from passive diffusion in the
following ways: 1) The transport of the drug occurs against a
concentration gradient; 2) the transport mechanism can become
saturated at high drug concentration; and 3) a specificity for a
certain molecular structure can promote competition in the presence
of a similarly structured compound. This, in turn, can decrease the
absorption of a drug.
Mechanisms of Drug Absorption
1) Carrier-Mediated or Active Transport
PHYSICOCHEMICAL FACTORS AFFECTING DRUG
ABSORPTION
• The pH-Partition Hypothesis on Drug Absorption
1. The gastrointestinal and other biologic membranes act like
lipid barriers.
2. The un-ionized form of the acidic or basic drug is preferentially
absorbed.
3. Most drugs are absorbed by passive diffusion.
4. The rate of drug absorption and amount of drug absorbed are
related to the drug’s oil–water partition coefficient (i.e., the more
lipophilic the drug the faster is its absorption).
5. Weak acidic and neutral drugs are absorbed from the
stomach, but basic drugs are not.
PHYSICOCHEMICAL FACTORS AFFECTING DRUG
ABSORPTION
• When a drug is administered intravenously, it is immediately
available to body fluids for distribution to the site of action. However,
all extravascular routes, such as oral, intramuscular, sublingual,
buccal, subcutaneous, dermal, rectal, and nasal routes, can
influence the overall therapeutic activity of the drug, primarily
because of its dissolution rate, a step that is necessary for a drug to
be available in a solution form. When a drug is administered orally in
a dosage form such as a tablet, capsule, or suspension, the rate of
absorption across the biologic membrane frequently is controlled by
the slowest step in the following sequence:
For very weak acids, pK a values greater than 8.0 are
predominantly un-ionized at all pH values between 1.0 and
8.0. Profound changes in the un-ionized fraction occur with pH
for an acid with a pKa value that lies within the range of 2.0 to
8.0. Although the fraction un-ionized of even strong acids
increases with hydrogen ion concentration, the absolute value
remains low at most pH values shown.
Estimation of Drug Absorption
• An antibiotic EMUMYCINE has a pKa of 4.
What would be its main absorption site?
?
Biopharmaceutical Drug Classification
• CLASS I DRUGS (HIGH SOLUBILITY AND HIGH
PERMEABILITY
• CLASS II DRUGS (LOW SOLUBILITY AND HIGH
PERMEABILITY)
• CLASS III DRUGS (HIGH SOLUBILITY AND LOW
PERMEABILITY)
• CLASS IV DRUGS (LOW SOLUBILITY AND LOW
PERMEABILITY)
Efflux Transporters
• More recently (33–37), the role of efflux transporters in influencing
the permeability and the overall bioavailability of drugs has emerged
and gained considerable attention. Among these transporters is Pgp, which is expressed on the luminal surface of normal intestinal
mucosa. Unlike absorptive transporters that increase the uptake of a
substrate from intestinal lumen, P-gp impedes uptake by returning
the portion of drug entering the mucosa back to the lumen in a
concentration-dependent manner. Two types of P-gp have been
observed in mammals: drug-transporting P-gp and phospholipid
transporting P-gp.
• The localization suggests that P-gp functionally can protect the body
against toxic xenobiotics by excreting these compounds into bile,
urine, and the intestinal lumen and by preventing their accumulation
in brain and testes. Thus, P-gp can have a significant role in drug
absorption and disposition in human and animals. An increasing
number of drugs have been shown to be substrate for P-gp.
Prodrugs
• Prodrugs are bioreversible derivatives of drug molecules that undergo
an enzymatic and/or chemical transformation in vivo to release the
active parent drug, which can then exert the desired pharmacologic
effect. In both drug discovery and development, prodrugs have become
an established tool for improving physiochemical, biopharmaceutical, or
pharmacokinetic properties of pharmacologically active agents. The
rationale behind the use of a prodrug is generally to optimize
absorption, distribution, metabolism, and excretion (ADME) processes.
• Prodrugs are usually designed to improve oral bioavailability due to
poor absorption from the gastrointestinal tract. Prodrugs are now an
established concept to overcome barriers to a drug’s usefulness. About
5% to 7% of drugs approved worldwide can be classified as prodrugs,
and the implementation of a prodrug approach in the early stages of
drug discovery is a growing trend.
Type of Prodrugs
• Hard Prodrug: A hard prodrug is a biologically active compound
with a high lipid solubility or high water solubility having a long
biologic half-life.
• Soft Prodrug: A soft drug is a biologically active compound that is
biotransformed in vivo in a rapid and predictable manner into
nontoxic moieties.
• Carrier-Linked Prodrug: A carrier-linked prodrug is a compound
that contains an active drug linked to a carrier group that can be
removed enzymatically. These prodrugs are generally esters or
amides, and such a prodrug would have greatly modified lipophilicity
due to the attached carrier. The active drug is realized by hydrolytic
cleavage either chemically or enzymatically.
• Mutual Prodrug: Two, usually synergistic, drugs are attached to
each other. A bipartite or tripartite prodrug is one in which the carrier
is a synergistic drug with the drug to which it is linked.
Major Objectives of Prodrug Design
•
•
•
•
•
•
•
IMPROVED BIOAVAILABILITY
IMPROVED AQUEOUS SOLUBILITY
IMPROVED PASSIVE INTESTINAL ABSORPTION
PROTECTION AGAINST FAST METABOLISM
IMPROVEMENT OF TASTE AND ODOR
CHANGE OF PHYSICAL FORM OF API
REDUCTİON OF PAIN ON INJECTION
A simplified representative illustration of the prodrug concept.
•
The drug–promoiety is the prodrug that is typically pharmacologically inactive.
In broad terms, the barrier can be thought of as any liability or limitation of a
parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic
performance, and which has to be overcome for the development of a
marketable drug. The drug and promoiety are covalently linked via
bioreversible groups that are chemically or enzymatically labile, such as those
shown here. The ‘ideal’ prodrug yields the parent drug with high recovery
ratios, with the promoiety being non-toxic
Common functional groups on parent drugs that are amenable
to prodrug design (shown in green)
•
Most prodrug approaches
require a ‘synthetic handle’
on the drug, which are
typically heteroatomic
groups.
Examples: Prodrugs for improved lipophilicity or permeability
Examples: Prodrugs for improved aqueous solubility
Other selected examples
•
Capecitabine (Xeloda) is a prodrug that has reduced gastrointestinal toxicity
and high tumour selectivity. The enzymatic bioconversion pathway initiates in
the liver, where human carboxylesterases 1 and 2 (CES1 and CES2) cleave the
ester bond of the carbamate142. This is followed by a fast, spontaneous
decarboxylation reaction resulting in 5′-deoxy-5-fluorocytidine (5′-dFCyd)144.
Generation of the parent drug continues in the liver, and to some extent in
tumours, by cytidine deaminase (CDA), which converts 5′-dFCyd to 5′deoxyuridine (5′-dFUrd). Finally, thymidine phosphorylase (dThdPase; also
known as ECGF1) liberates the active drug 5′-fluorouracil in tumours7,144

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