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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5919_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 2
Fundamentals of Pharmacokinetics and Drug Delivery
Asha, Puneet Goyal, Pooja, and Ravi Dabas
Abstract
Pharmacokinetics, a subfield of pharmacology, is the study of drug absorption, distribution, metabolism,
and excretion kinetics, including the magnitude and speed of each of these processes. The Greek elements
“pharmakon” (drug) and “kinesis” (movement) are the origin of the English term “pharmacokinetics,”
which describes the movement of a drug. Pharmacokinetics is the mathematical study of the timedependent variation in medication concentrations. So, to sum up, pharmacokinetics is the study of how
medications enter, travel through, and are eliminated from the body by means of metabolism and excretion.
Pharmaceuticals depend on pharmacokinetics research since it determines the dosage, mode of administration, time of peak effect, duration of action, and frequency of drug administration. Principles of pharmacokinetics center on variations in drug concentration brought about by drug absorption, distribution, and
elimination throughout time. There are two primar y ways that drugs and chemicals get beyond biological
membranes: simple transfer and specialized transport. The process by which an unaltered medication enters
the bloodstream from the place of administration is known as absorption. Due to the porosity of the
capillaries, even big lipid-insoluble or ionized medicines are absorbed, whereas lipid-soluble medications
readily pass through the capillary endothelium. The process by which medications enter extravascular fluids
and tissues and leave the bloodstream is known as distribution. This critical pharmacokinetic phase affects
not only the organs involved in metabolism and excretion but also the way that medicines reach their target
areas. The process of changing a substance’s chemical form to one that is more water soluble for simpler
excretion is called metabolism. Particularly, “biotransformation” describes the chemical alterations that
foreign substances go through in the body. There are two main stages of biotransformation. Phase I consists
of processes involving oxidation, reduction, and hydrolysis that add or reveal tiny polar functional groups
(such -OH and -NH2). In order to prepare lipid-soluble medications for Phase II reactions or direct
excretion, this phase alters them to make them more polar. Conjugation is the process by which polar
endogenous compounds (such as sulfate or glucuronic acid) are joined to medications or their Phase I
metabolites in Phase II. This step results in readily excreted conjugates that are soluble in water. The process
of permanently eliminating medications and their metabolites from the body is called excretion. Watersoluble and ionized compounds are excreted more readily by excretory organs—apart from the lungs—than
lipid-soluble ones, which must first be converted into water-soluble forms in order to be excreted more
easily. The drug’s concentration in the body has an impact on pharmacokinetic processes (ADME), and
how that concentration influences the process rate is known as the process order. Key pharmacokinetic
parameters may be computed and the time course of medications in the body can be expressed quantitatively using pharmacokinetic models. Pharmacokinetics is determined by three factors: elimination, distribution and absorption.
Key words Absorption, Distribution, Metabolism, Excretion, Biotransformation
29
30 Asha et al.
1 Introduction
In the branch of science that examines what happens to a material
after it is given to a living thing, pharmacokinetics is the study of
drug distribution, metabolism, excretion, and absorption kinetics,
including the magnitude and rate of each of these processes. It is
necessary to study the rate of drug absorption because, although it
is not always ideal, faster drug absorption results in a faster onset of
medication effect, which is necessary for treating acute disorders
and in emergency situations. Researching the degree of drug
absorption is crucial since the amount of the drug that is absorbed
and enters the systemic circulations is what causes the pharmacological effect [
The pace of medication distribution to its site of affection
impacts the beginning of action and the extent of distribution
defines the degree of the effect. The frequency of drug administration needed during multiple drug administration to make up for
the drug that is removed is determined by the rate of drug elimination. Drugs that are removed more quickly need to be administered
often in order to maintain an effective drug concentration during
the course of many administrations.
The primary pharmacological principle in the therapeutic use of
pharmaceuticals is to pick the appropriate dose regimen for each
individual animal based on the patient’s personal information and
the medication phar macokinetic properties. The patient’s unique
pharmacokinetic parameter can be ascertained during drug administration by using the blood drug concentration measured at a
certain time point.
The combined effects of drug distribution and elimination
processes (metabolism and excretion), which usually happen after
intravenous (IV) injection, are referred to as “drug disposition.”
1].
2 Pharmacokinetic Principles
The main focus of pharmacokinetic principles is how changes in
drug concentration over time are caused by drug absorption, distribution, and elimination. Understanding the relationship
between drug effects and concentration in the body is essential.
Pharmacokinetics is the mathematical study of how drug concentrations change over time. The extent and speed of ADME processes, the right doses and schedules for drugs, the concentrations
of both therapeutic and toxic drugs, the levels of drugs in bodily
fluids and tissues, the half-life and duration of action of drugs, the
impact of diseases on drug kinetics, the duration of drug withdrawal in food animals and the types of drug interactions are all
determined by pharmacokinetic principles [
3] (Fig. 1).
Fundamentals of Pharmacokinetics and Drug Delivery 31
Fig. 1 Flowchart for principles of pharmacokinetics
2.1 Application of the Pharmacokinetic Principle in the Biomedical Fields
• Design and evaluation of dosage forms
• Evaluations of drug formulation
• Pharmacological
• Dosing regimen
3 Cell Membrane/Biological Membrane
The hydrocarbon chains of the amphipathic lipids in the plasma
membrane are orientated inward to produce a continuous hydrophobic phase, while the hydrophilic heads of the lipids are oriented
outward. The bilayer’s individual lipid molecules differ depending
on the specific membrane and have the ability to migrate laterally,
giving the membrane flexibility and fluidity, high relative impermeability to highly polar compounds, and high electrical resistance.
Membrane proteins that are integrated into the bilayer function as
transporters, ion channels, or receptors to trigger chemical or
electrical signaling pathways and offer specific sites for medication
action.
Organs, cells,
categorized and organized by highly specialized molecular barriers
called biological membranes. Medication must pass through one or
more of these membranes in order to reach its intended location,
regardless of the mode of administration. These barriers can be as
simple as a single layer of cells found in enterocytes and renal
tubular epithelial cells, or as complex as many layers of cells found
in the skin, vagina, and placenta. The membranes of individual cells,
mitochondria, and the nucleus are examples of situations where the
barrier can be much thinner. Polar lipid molecules, such as
testing
design
and intracellular activity within the body are
32 Asha et al.
phospholipids, are the main building blocks of biological membranes. These molecules create a bilayer. The hydrophobic (fatty
acid) tails of this bilayer face inward, while the hydrophilic (waterattracting) heads are directed toward the membrane surfaces.
Drug molecules can be carried by bulk water flow, as most cell
membranes are reasonably permeable to water either by diffusion
or flow caused by hydrostatic or osmotic variations across the
membrane. The main method by which medications penetrate the
majority of capillary endothelial membranes is by this type of transport. However, trans-capillary movement is restricted to unbound
drug since bound proteins and drug molecules are too big and
polar for this kind of transport to happen. The amount of paracellular transfer across intercellular gaps is so great that blood flow,
rather than other parameters, is the limiting factor for transit across
most capillaries. This kind of transport plays a crucial role in the
kidney’s glomerular membrane filtration, as will be discussed later.
However, there are significant exceptions to this general rule in
capillary diffusion because certain tissues have “tight” intercellular
connections and have restricted paracellular transit. Tight junctions
are found in the capillaries of the central nervous system (CNS) and
many dif ferent types of epithelial tissues.
3.1 Passage of Drugs Across Biological Membranes
A medication must cross cell membranes in order to be absorbed,
distributed, metabolized, and excreted. Therefore, it is crucial to
understand the mechanisms by which medications cross membranes as well as the physicochemical characteristics of molecules
and membranes that affect this transfer. A drug’s molecular size and
structure, degree of ionization, relative lipid solubility of its ionized
and non-ionized forms, and ability to bind to tissue proteins are its
defining properties.
It goes without saying that a medicine must cross the plasma
membrane of the cell in order to enter the cell. Additional cell layers
(skin) or a single layer of cells (intestinal epithelium) may act as
barriers to the transport of drugs. Since pharmaceuticals generally
travel through cells rather than between them, there are many
common properties that characterize drug dispersion and transport
across these different barriers, despite their structural variations.
Thus, the common barrier is represented by the plasma membrane.
There are two primary ways that drugs and chemicals get beyond
biological membranes: simple transfer and specialized transport
2).
(Fig.
3.1.1 Simple Transport A. Diffusion
One of
the main ways that medications get through biological
membranes is by diffusion, often known as passive diffusion. Under
the influence of the concentration gradient, lipid-soluble compounds and unionized pharmaceuticals pass through the
Fundamentals of Pharmacokinetics and Drug Delivery 33
Fig. 2 Flowchart of methods by which drugs move across the plasma membrane
membrane in this manner without the requirement for energy or
carriers. Until an equilibrium is attained, drugs diffuse from areas of
higher concentration to areas of lower concentration. This process
has no structural character and is not saturable. Water-soluble
medications struggle to permeate lipid membranes, but highly
lipid-soluble pharmaceuticals also diffuse poorly due to their insolubility in bodily fluids. It is easier for drugs with molecular weights
b
etween 100 and 400 Da to diffuse than for bigger molecules.
Diffusion is enhanced by thin membranes and large surface areas,
such as those seen in the lungs and intestine.
When taking into account variables like concentration gradient,
diffusion coefficient, lipid solubility, surface area, and membrane
thickness, Fick’s first law of diffusion provides the best description
of the passive diffusion of drug molecules over a biological
membrane.
Rate of diffusion molecules per unit timeð = C
A × D × K
=
Where, C
is the higher concentration, C2 is the lower concentra-
1
tion, and the difference (C
=w
m
T
- C2) represents the concentration
1
Þ
- C
ð
1
Þ
2
gradient across the membrane. A is the membrane’s surface area,
D is the drug’s diffusion coefficient, K
/w is the lipid-water parti-
m
tion coefficient, and T is the membrane thickness.
The percentage of drug ionized at a particular pH in bodily
fluids and the ratio of ionized to unionized drug are found using
the Henderson-Hassel Balch equation:
For weak acidic drug
pK
- pH = log of concentration of unionized drug
a
=concentration of ionized drug
%ionized drug = 100=1 þ antilog pK
- pHðÞ
a
34 Asha et al.
For weak basic drug
3.1.2 Specialized Transport
pH - pK
= log of concentration of unionized drug
a
=concentration of ionized drug
%ionized drug = 100=1 þ antilog pH - pK
ðÞ
a
B. Filtration
Drugs are filtered when they pass through membrane
or pores
as a result of osmotic pressure variations or hydrostatic
channels
pressure. It mostly affects passive transport-related small molecules
(Mol. wt. <100). It is crucial for the renal excretion (glomerular
filtration) and medication elimination from cerebrospinal fluid,
albeit less significant for the majority of medicines.
A. Active Transport
Solutes require carriers, typically membrane proteins, in the
energy-dependent process of active transport, which allows them
to move against the concentration gradient (from lower to higher
concentration). Because carriers only transfer medications with
particular chemical structures, this mechanism is energy-intensive
and structure-specific. The process can become saturated since
there are only so many carriers, particularly at high drug concentrations where medicines with similar structures may compete for the
same carriers. For large hydrophilic, polar, or electrolyte compounds like methyldopa, L-dopa, and several antimetabolites,
active transport is essential. It is also essential for the excretion of
some medications from the central nervous system and for renal
and biliary excretion.
There are two categories of active transport: primary and secondary. In primary active transport, a carrier moves against the
concentration gradient of a single material by utilizing the energy
from ATP hydrolysis. A driving solute (such as Na, K, or Ca) and a
substrate share a carrier in secondar y active transport. The driving
solute uses the electrochemical gradient produced by cell energy to
propel the substrate’s movement. Co-transport (symport) is the
term used when both move in the same direction; countertransport (antiport) is the term used when they move in opposite
directions. Drugs are less dependent on secondary active transport
than ions and nutrients (Table
1).
B. Facilitated D
A car
rier-mediated transport mechanism called “facilitated dif-
iffusion
fusion” transfers materials downward, following their concentration gradient, without requiring energy. The concentration
Fundamentals of Pharmacokinetics and Drug Delivery 35
Table 1
Difference between simple diffusion and active transport
Serial
No.
Features Simple diffusion Active transport
1. Energy Energy independent (passive
process)
2. Carrier Not required Required
3. Movement of drug Along the concentration
gradient
4. Saturation Non-saturable process Saturable process
5. Competitive
inhibition
6. Structure specificity Not required Required
7. Nature and type of
drug
8. Occurrence Wide occurrence in body Limited to certain parts
Do not occur May occur
Lipid soluble and unionized Mainly hydrophilic, polar and
Energy dependent (active process)
Against the concentration gradient
electrolyte
gradient drives the passive process of membrane crossing even
though a carrier helps. It can move materials that cannot disperse
on their own and is quicker than ordinary diffusion. It is structurespecific, saturable, and competitive with other agents of a similar
nature to active transport. Nevertheless, unlike the symports and
antiports of active transport, assisted diffusion uses uniports, which
only move a single molecule at a time. Examples include the uptake
of
specific vitamins and the entrance of glucose into red blood cells.
One of the less important drug transport mechanisms is facilitated
diffusion.
C. Pinocytosis
A small transpor
t process called pinocytosis forms extracellular
drug droplets into vesicles by engulfing them in a section of the cell
membrane. The vesicles are subsequently internalized and transferred between cell membranes. Phagocytosis and this process are
comparable; however, liquid droplets are used in place of solid
particles. Sometimes, endocytosis is used to refer to both processes.
In addition to having competitive saturation kinetics and some
structural selectivity, pinocytosis consumes cellular energy. It is in
charge of taking in big proteins, some medications, such as insulin,
and macromolecular nutrients. It also absorbs vaccines, like the
Sabin Polio vaccine.
36 Asha et al.
4 Routes of Drug Administration
There are several ways to administer drugs, and each has pros and
cons of its own [
15].
4.1 Oral (Enteral) Versus Parenteral Administration
4.2 Various Routes of Drug Administration
• Oral administration is the most popular and practical approach.
Although it has benefits like cost-effectiveness and safety, food,
digestive enzymes, and medication solubility may impede its
absorption. Although controlled-release formulations may
result in patient variability, they can enhance drug absorption.
When oral delivery is not possible, there are several routes that
allow faster absorption or avoid the liver’s first-pass effect: sublingual and rectal.
• When oral administration is not an option or is an emergency,
peripheral administration (injection) provides quick, accurate
drug delivery. Risks associated with intravenous injections
include possible responses and the dose’s irreversibility, but
they also provide regulated, immediate effects and avoid problems with absorption. Subcutaneous and intramuscular injections are two other parenteral techniques that provide slower,
persistent absorption. Moreover, specific organs or tissues can be
targeted with intrathecal, topical, intraarterial, and pulmonary
applications. Depending on the substance and circumstance,
each approach has advantages and disadvantages.
1. Oral (enteral) administration is the most common, convenient, and economical method, being noninvasive and easy
for self-administration. However, absorption can be inconsistent due to factors like food, enzymes, or pH and first-pass
metabolism in the liver can reduce drug efficacy. It’s also
unsuitable for patients who are vomiting or unconscious.
2. Sublingual administration provides rapid absorption directly
the bloodstream, bypassing
into
first-pass metabolism, but it
is limited to small doses and certain drugs.
3. Rectal administration is useful for patients who can’t take drugs
orally and partially bypasses first-pass metabolism, though
absorption can be irregular and may irritate the rectal mucosa.
4. Intravenous (IV) administration
ensures immediate
and complete bioavailability, allowing controlled and accurate drug
delivery, but it requires aseptic conditions and skilled administration, with risks of infection, rapid adverse reactions, and
irreversibility once the drug is administered.
5. Intramuscular (IM) injections of
fer rapid absorption for aqueous solutions and sustained release for depot formulations,
though they may cause pain, tissue damage, and slower absorption in obese individuals, with a risk of accidental injection into
blood vessels.
Fundamentals of Pharmacokinetics and Drug Delivery 37
6. Subcutaneous (SC) injections provide slower, sustained drug
release and are less invasive than IV or IM routes, but they are
limited to non-irritating drugs and can be painful, with a
restricted volume of administration.
7. Inhalation offers rapid absorption due to the large lung surface
area and is ideal for local delivery to the lungs, such as in asthma
treatment, but it requires proper technique and dose control
can be challenging.
8. Topical administration provides localized effects, minimizing
systemic side effects, with
transdermal
patches offering controlled, sustained release, though absorption is slow through
intact skin and limited to lipid-soluble drugs.
9. Intrathecal administration delivers drugs directly into the cerebrospinal
fluid (CSF), bypassing
the blood–brain barrier, which
is useful for spinal anesthesia or CNS infections, but it requires
expert administration and carries a high risk of complications.
10. Intraar terial administration targets specific organs or tissues,
as in
such
treating liver tumors, but it is technically challenging
and risky, with potential for local tissue damage.
Each route has specific benefits based on the drug and the
patient’s condition, but they also come with inherent limitations and risks.
5 Absorption
5.1 Factors Affecting Absorption of Drugs
5.1.1 Physio-chemical Characteristics
The process by which an unaltered medication enters the bloodstream from the place of administration is known as absorption.
Drug absorption is necessary for all systemic routes, with the
exception of intravascular ones, in order for the medication to
reach its target in the circulation and start working. The effectiveness of a medicine is dependent on its pace and degree of absorption; a drug that absorbs slowly may not reach its minimal effective
concentration, whereas a substance that absorbs quickly may attain
therapeutic levels quite soon. Drugs must dissolve in bodily fluids
in solid forms, such as powders, capsules, and tablets, in order for
them to be absorbed, regardless of the mode of administration [
2].
Several factors affect the rate and degree of medication absorption.
Absorption is influenced by molecule size, pK, and lipid solubility.
Drugs that are unionized and lipid-soluble are absorbed more
quickly.
38 Asha et al.
5.1.2 Dosage Form
Compared to oily, suspension, or solid forms, drugs in aqueous
solutions are absorbed more quickly. Absorption is also influenced
by the rate of dissolution; liquids often absorb more quickly than
pills or sustained-release goods.
5.1.3 Concentration and Volume
5.1.4 Blood Flow By preserving the concentration gradient, improved blood flow to
A steeper concentration gradient causes higher drug concentrations
and quantities to be absorbed more quickly.
the absorption site improves medication absorption.
5.1.5 Surface Area Faster absorption is achieved by larger absorbent surfaces, such as
the intestine as opposed to the stomach.
5.1.6 Administration Route
Different routes have different rates of absorption; pulmonary and
intramuscular (IM) routes absorb drugs more quickly than subcutaneous (SC) or oral methods.
5.1.7 Disease States By changing pH, membrane permeability, or blood flow, illnesses
such acid-base imbalances, infections, and cardiovascular disorders
can have an impact on absorption.
5.2 Gastrointestinal Tract
For systemic medications, the oral route is frequently used. Drugs
enter the stomach through the esophagus and mouth after consumption. Although absorption is supported by the abundant
blood supply and thin epithelium of the oral mucosa, significant
absorption is limited by the mouth’s brief period of contact.
Because of its quick passage time, the esophagus does not absorb
medicines either. The gastrointestinal (GI) tract’s epithelial lining
serves as the primary barrier. According to the pH-partition
hypothesis, acidic medications are better absorbed in the stomach
and basic pharmaceuticals in the intestine. Lipid-soluble and
unionized drugs are absorbed by diffusion. The majority of medications are instead absorbed in the intestine, which has a big surface
area and ideal circumstances, whereas stomach absorption is
restricted by the thick gastric mucosa and small surface area [
Food can
slow down and dilute absorption in the GI tract.
5].
While digestive juices aid in the dissolution of medications, they
can also render certain inactive (such as insulin and penicillin-G).
Reduction of absorption can also occur from drug metabolism by
gut bacteria or enzymes. While high intestinal motility can reduce
absorption, rapid gastric emptying often improves it. Drugs taken
concurrently may have an impact on absorption and varying reactions may result from variables such as drug size, dosage for m, GI
tract variations, and pathological states.