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Fundamentals of Pharmacokinetics and Drug Delivery 39
5.3 Parenteral Sites
5.4 Pulmonary Sites (Alveoli)
5.5 Topical Sites
Because medicines are placed close to capillaries, absorption from
intramuscular (IM) and subcutaneous (SC) locations is typically
rapid. 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. Most substances that are more than 20,000 Da reach the lymphatic system.
IM medication absorption happens quickly—typically in
10 to 30 minutes, depending on blood flow. Because there is less
blood flow, SC absorption is slower, which is useful for depot
preparations. Vasoconstrictors such as adrenaline slow down SC
absorption; however, hyaluronidase can increase it by spreading
the medication. Heat, massage, or exercise can increase blood
flow to the injection site and speed up absorption; cooling, immobility, or the use of a tourniquet slows it down.
Aerosols and volatile anesthetics are two examples of drugs that are
rapidly absorbed when inhaled. Because of their tiny molecular size,
high lipid-to-water ratio, vast surface area, and high permeability of
the alveoli, volatile anesthetics are rapidly absorbed. Particle size is
important for aerosols because smaller particles enter the lungs
deeper and are quickly absorbed from the alveoli, while bigger
particles remain in the upper respiratory tract.
Although the main purpose of topical medicine administration is to
cause local effects, some medications can also have systemic effects
by being absorbed through the skin or mucous membranes. Lipid
solubility is the primary factor that deter mines systemic absorption
from topical administration; medicines that are insoluble in lipids
usually penetrate poorly. The keratinized epidermis of the skin
serves as a barrier, yet rubbing, occlusive dressings, or iontophoresis can improve absorption. Dimethyl sulfoxide (DMSO) is one
solvent that can help with penetration. Skin injury or inflammatory
disorders might also increase absorption. Due to their thinness and
high vascular density, mucous membranes typically absorb drugs
more quickly than the skin, but this can occasionally result in
unfavorable systemic side effects.
6 Distribution
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 [
6].
40 Asha et al.
6.1 Factors Affecting Distribution of Drugs
6.1.1 Physicochemical Properties of the Drug
6.1.2 Binding to Plasma and Tissue Proteins
6.1.3 Blood Flow and Organ Size
Except in the CNS, drugs with molecular weights less than
500–600 Da typically pass-through capillary membranes with
ease. Their mobility from extracellular fluids into cells is contingent
upon their molecular size, lipophilicity, and ionization. The
pH-partition hypothesis states that whereas acidic medications
concentrate in alkaline fluids, basic pharmaceuticals reach acidic
tissues and fluids (where they become ionized and confined).
Medications in blood can either be free or attached to plasma
proteins. Free medications can be metabolized and eliminated, are
diffusible and have pharmacological activity. Because of their
increased size, bound medicines are inert, cannot disperse, and
cannot be metabolized or excreted. If the concentration of a drug
in a tissue is greater than that of the plasma, it is said to be localized
in that tissue [
8]. For example, tetracyclines can build up in dental
tissues during a child’s or infant’s tooth development, causing the
teeth to permanently discolor from brown to yellow.
The size and blood flow rate of the organs determine how drugs are
distributed to them. Lipid-soluble medications quickly equilibrate
in highly perfused organs such as the brain, kidneys, liver, heart,
adrenal glands, and lungs. The equilibration process takes longer
for tissues with moderate perfusion, such as muscle and skin, and
even longer for tissues with poor perfusion, including adipose
tissue, bones, and teeth.
6.1.4 Specialized Compartments and Barriers
• Blood–Brain Barrier (BBB): Endothelial cells and the astrocyte-
covered basement membrane that serve as protection form the
BBB’s tight connections. Generally speaking, it permits lipidsoluble medications to pass through while polar or ionized
medications do not. Specific carriers are used to carry some
medications and endogenous compounds, and some parts of
the brain can flow through the blood-brain barrier. Older people
and neonates are less effective at using the barrier.
• Blood-Cerebrospinal Fluid (CSF) Barrier: This barrier, which is
made up of the choroid plexus, features tight connections
between choroidal cells but open junctions between capillary
endothelial cells. Lipid-soluble medications can pass through it
and into the CSF, but because CSF is always flowing, drug
concentrations in the CSF are often lower than in the brain.
• Placental Barrier:
Similar to the BBB, the placental barrier is
made up of trophoblastic cells. Water-soluble medications use
carrier-mediated transport, whereas lipid-soluble medications
pass easily. Certain lipid-insoluble medications may only pass in
small quantities, particularly if they are present for long periods
of time or in high concentrations. Compared to the BBB, the
barrier is less restrictive.
Fundamentals of Pharmacokinetics and Drug Delivery 41
• Other Barriers: Drug penetration is restricted by structures such
as the eyes, testicles, and prostate. Moreover, drugs have
restricted access to middle ear fluid, bronchial secretions, and
pericardial fluid. Compared to water-soluble medicines, lipidsoluble medications are more easily absorbed into these tissues.
6.1.5 Specialized Transport Systems
Certain medications are actively absorbed by specialized transport
mechanisms, resulting in concentration in particular tissues. Thyroid cells, for instance, actively absorb iodine [11].
6.1.6 Disease States Drug distribution can be affected by diseases. For example, the
blood–brain barrier becomes more porous in meningitis and
encephalitis, which makes it possible for polar antibiotics such as
penicillin-G to enter the brain. Reduced plasma protein binding in
hypoalbuminemia may result in elevated amounts of free
medications.
6.1.7 Physiological Factors
Because of their immature brains and increased cerebral blood flow,
babies have more drug penetration into the brain. Drug distribution in older people is impacted by decreased blood–brain barrier
effectiveness and decreased protein levels. Despite modest perfusion rates, obesity can lead to the accumulation of lipophilic medicines in adipose tissue [
13]. Due to the expanding uterus, placenta,
and fetus during pregnancy, the volume of distribution increases,
forming a distinct compartment for the distribution of drugs.
7 Metabolism/Biotransformation
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 molecular alterations that foreign substances go through in the body. The term
“metabolism“is more general and encompasses changes to endogenous molecules like as proteins and lipids as well as
xenobiotics [
7].
7.1 Functions of Metabolism
1. Inactivation: Converts active drugs to inactive forms (e.g.,
phenobarbital, morphine).
2. Bioactivation: Converts drugs to more active forms (e.g.,
codeine, isoniazid).
3. Pharmacological Activation: Converts inactive pro-drugs to
active forms (e.g., enalapril, levodopa).
4. No Change:
Converts
active drugs to equally active forms (e.g.,
diazepam, digitoxin).
5. Change in Activity: Converts active drugs to metabolites with
different pharmacological effects (e.g., iproniazid).
42 Asha et al.
7.2 Sites of Metabolism
7.3 DrugMetabolizing Enzymes
7.3.1 Microsomal Enzymes
7.3.2 Non-microsomal Enzymes
All bodily tissues have some level of metabolic activity, but the liver
is the primary location for drug metabolism because it has a large
number of metabolizing enzymes. Because there are fewer enzymes
in other organs, extra-hepatic metabolism is less relevant. While
some drug metabolism does occur in the nuclear envelope, plasma
membrane, and mitochondria, the majority of it takes place in the
cytosol and smooth endoplasmic reticulum. There is additional
non-enzymatic metabolism, such as the spontaneous decomposition of atracurium in plasma [
9].
Drug-metabolizing enzymes are classified into two types.
These enzymes, which are present in the smooth endoplasmic
reticulum of the liver and other tissues, are essential for the majority
of oxidative processes, some reductive and hydrolytic reactions, and
glucuronide conjugation. Glucuronyl transferase and monooxygenases are two examples.
These enzymes, which are found in the cytoplasm, mitochondria,
bodily fluids, and other tissues, participate in all conjugative reactions other than glucuronidation and carry out more reductive,
hydrolytic, and oxidative reactions.
7.4 Pathways of Biotransformation
8 Excretion
Drug biotransformation occurs in two major phases.
1. Phase I: These enzymes participate in all conjugative reactions
except glucuronidation and perform additional reductive,
hydrolytic, and oxidative reactions. They are present in the
cytoplasm, mitochondria, body fluids, and other organs.
2. Phase II: involves conjugation, which is the process by which
medicines or their Phase I metabolites are joined to polar
endogenous molecules (such as glucuronic acid or sulfate).
This step results in readily excreted conjugates that are soluble
in water.
Phase II typically results in the drug being inactive, but Phase I
may cause no change, inactivation, or bioactivation. While some
medicines go through both phases, others might only go through
one. Through these processes, a single medication can create several metabolites [
14].
The process of permanently eliminating medications and their
metabolites from the body is called excretion. Water-soluble and
ionized compounds are excreted more readily by excretory
Fundamentals of Pharmacokinetics and Drug Delivery 43
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.
8.1 Routes of Excretion
8.1.1 Renal Excretion of Drugs
8.1.2 Extra-Renal Excretion of Drugs
Drugs are removed from the body by a variety of pathways, including the kidneys, lungs, bile, and intestines, either unaltered or as
metabolites. Renal excretion is the word used to describe elimination via the kidneys; extra-renal or non-renal excretion is the term
used to describe elimination through other organs.
The main method of drug removal, particularly for tiny,
non-volatile, water-soluble compounds, is renal excretion. Tubular
secretion, tubular reabsorption, and glomerular filtration are the
three mechanisms involved.
A. Glomerular filtration: Drugs that are not protein-bound are
non-selectively filtered into renal tubules through glomer
filtration, which
is fueled by the hydrostatic pressure of blood.
ular
B. Tubular secretion: Relying on renal blood flow, tubular secre-
tion actively moves some medications from blood to the tubular lumen, independent of concentration gradients.
C. Tubular reabsorption: Tubular reabsorption, which happens
passively for lipid-soluble medications or actively for some
endogenous compounds, brings medications from the tubular
fluid back into the bloodstream and prolongs their half-lives.
A. Biliary excretion: Through bile, drugs and their metabolites are
eliminated, primarily by active processes. Large molecules and
highly polar, water-soluble conjugates are expelled more easily.
B. Pulmonary excretion: Diffusion is how gases and volatile
substances—such as inhalation anesthetics—are expelled from
the body through the lungs. The solubility, blood flow, and
respiration all affect the rate at which lipid-soluble medications
leave the body unaltered.
C. Mammary excretion: Medicines can enter milk through a small
opening and impact breastfeeding babies; weakly basic medicines concentrate more because of the acidity of milk. Drugs
that are lipophilic can attach to milk fat.
D. Salivary excretion: Certain drugs can enter saliva through
active secretion, although most enter through passive diffusion. Saliva excretion in ruminants might upset the microbiota
in the rumen.
E. Gastrointestinal excretion:
Drugs can enter the GI system from
blood and then be recycled or eliminated in feces, commonly
following parenteral delivery.
44 Asha et al.
F. Other excretion routes: Sweat, tears, and other fluids contain
trace amounts of drug residue. It is possible to find certain
heavy metals in nails and hair.
An alternate method is to utilize particular pharmacokinetic
principles to examine plasma drug concentration–time data in
order to explore the rate and extent of individual pharmacokinetic
parameters, as this is a complex process.
9 Plasma Drug Concentration–Time Profile
A drug’s concentration at the site of action determines the start,
strength, and duration of its effects. Since it is difficult to take direct
tissue samples, plasma drug levels are taken as a rough estimate.
Plotting the drug concentrations against time (X-axis) and measuring the drug levels in plasma (Y-axis) at different times results in the
plasma drug concentration–time curve [
A medication that is given orally or through an extravascular
route (IM, SC, IP, etc.) enters the bloodstream gradually and raises
the plasma drug concentration until it reaches a peak. The medication is transported to tissues and removed during absorption. The
absorption phase, where absorption exceeds distribution and elimination, is represented by the ascending portion of the curve preceding the peak. The elimination phase, in which elimination
surpasses absorption, is represented by the descending section
that follows the apex. The rates of absorption (Ka) and elimination
(ẞ) are shown by the slopes of these phases, respectively (Fig.
10].
3).
9.1 Minimum Effective Concentration (MEC)
9.2 Maximum Safe Concentration (MSC) or Minimum Toxic Concentration (MTC)
9.3 Maximum
Plasma Concentration
(C
or C
max
9.4 Area Under the Curve (AUC)
pmax
)
MEC is the minimum plasma drug concentration required to
achieve a therapeutic outcome. The smallest concentration needed
to impede microbiological growth is known as the smallest inhibitory concentration (MIC) for antimicrobial medications.
MSC or MTC is the plasma concentration at which a medication
starts to have harmful effects. Between MEC and MSC is where the
therapeutic range is located.
The dose, absorption rate (Ka), and elimination rate (β) all work
together to determine the maximum drug concentration in plasma.
When the rates of absorption and elimination are equal, it happens.
AUC is the entire area under the plasma concentration–time curve,
which shows how much medication has entered the systemic circulation overall.
Fundamentals of Pharmacokinetics and Drug Delivery 45
Fig. 3 Plasma drug concentration–time profile after oral administration of a
single dose of a drug. Abbreviation: C
MEC minimum effective-concentration; MSE maximum safe concentration; t
maximum/peak plasma concentration,
max
max
time of peak concentration; AUC area under-curve; K2 absorption rate constant:
elimination rate constant
9.5 Peak Effect
Peak effect is the maximum pharmacological reaction that a medication can produce; this is usually seen at peak plasma
concentration.
9.6 Time to
Maximum
Concentration (t
max
9.7 Onset of Action
)
The duration required for a medication to attain its maximum
plasma concentration. For medications treating acute illnesses, a
shorter half-life (tmax) is achieved through faster absorption.
When a drug’s plasma concentration surpasses the MEC, the pharmacological impact of the medication begins.
9.8 Onset Time
The amount of time that a medication takes to reach the MEC and
start having a pharmacological impact.
9.9 Duration of Action
The length of time a medication exerts its pharmacological effect,
typically corresponding to the period when its plasma concentration stays above the minimum effective concentration (MEC).
10 Order of Pharmacokinetic Processes
The drug’s concentration in the body influences pharmacokinetic
processes (ADME); the way this concentration impacts the process
pace is known as the process order. First-order, mixed-order, and
zero-order processes are the three primary categories.
46 Asha et al.
10.1 Zero-Order Kinetics
The process’s rate is fixed and independent of the drug’s concentration. Each unit of time processes a specific amount of drug, and
the half-life changes with drug concentration. This happens with
medications like alcohol and phenytoin, as well as in carriermediated processes when they are saturated.
10.2 First-Order Kinetics
A fixed percentage of the medication is metabolized over time
because the rate depends on the drug concentration. Most medications follow first-order kinetics, where the half-life remains constant
regardless of concentration
10.3 Mixed-Order Kinetics
This combines first- and zero-order kinetics. The drug exhibits
first-order kinetics at low doses; however, as concentrations
increase, carrier or enzyme saturation causes the drug’s kinetics to
shift to zero order. This is shown in medications such as riboflavin,
naproxen, and vitamin C.
11 Pharmacokinetic Models
The body moves drugs in a complex way, involving many pharmacokinetic processes (ADME) going on at once. Pharmacokinetic
models have been developed as a result of assumptions made about
drug movement in an attempt to simplify and explain these overlapping occurrences. These models provide a means of computing
important pharmacokinetic parameters and expressing the temporal course of medications in the body mathematically. Physiological
models, non-compartmental models, and compartmental models
are the three primary models utilized in drug analysis [
4].
11.1 Compartmental Models
11.1.1 OneCompartment Open Model
The conventional and extensively utilized approach for describing
drug pharmacokinetics is compartmental analysis. According to this
method, the body is separated into sections that can converse with
one another in both directions. Organs, tissues, and bodily fluids
can constitute multiple compartments; hence, tissues that share a
similar medication distribution pattern are combined into a single
hypothetical compartment. These compartments are mathematical
creations without physiological or anatomical meaning. Since most
medications can flow freely between compartments, one-, two-, or
three-compartment models—also known as open models—are typically employed to explain most drugs. Drug transport and elimination are thought to occur according to first-order kinetics.
The simplest pharmacokinetic model is the one-compartment open
model, which treats the body as a single homogenous unit. The
medication distribution across bodily fluids and plasma in this
model reaches equilibrium instantaneously and stays constant.
Modifications in tissue concentrations are directly reflected in
Fundamentals of Pharmacokinetics and Drug Delivery 47
variations in plasma drug levels. Whether a drug is given intravenously as a bolus or extra vascularly, this model describes the plasma
levels following a single dose and is applicable to pharmaceuticals
that distribute quickly throughout the body.
A. Intravenous bolus administration: When a medicine is admi-
nistered intravenously as a bolus, the whole dose enters circulation and reaches tissues promptly. On semi-logarithmic
paper, the resulting drug concentration–time curve displays a
monophasic exponential decline and is a straight line. The drop
is a reflection of the elimination phase—also known as drug
elimination. Since the distribution phase happens too quickly
to show on the graph, it is usually ignored. The drug concentration at time zero is represented by the zero-time intercept,
and the slope of the line indicates the elimination rate constant.
B. Extravascular administration: When administering drugs
extravascularly
(by mouth,
intramuscular injection, or subcutaneous injection), the drug must be absorbed before entering
the bloodstream. Two exponents—one for absorption
(Ka) and one for elimination (ẞ)—describe the change in
drug concentration over time for medications that adhere to
the one-compartment model.
11.1.2 TwoCompartment Open Model
The body is divided into a central compartment, which contains
blood; a peripheral compartment, which contains less perfused
tissues like skin, muscles, and bone; and a central compartment,
which contains highly perfused organs like liver, kidneys, lungs,
heart, and brain. Medications are injected or absorbed into the
central compartment, which quickly comes into equilibrium with
the organs within. While distribution between the central and
peripheral compartments happens slowly and is controlled by
first-order rate constants (k12 for movement from central to
peripheral and k21 for the opposite), elimination only occurs
from the central compartment.
A. Intravenous bolus
administration: When
an intravenous bolus
is administered, the plasma drug concentration in a
two-compartment model decreases biexponentially. Distribution causes a sharp initial decline (central to peripheral), while
elimination causes a delayed terminal fall. The elimination
phase is the phase for the curve’s terminal linear portion. The
residuals method (feathering technique) can be used to compute the initial drug concentration (C0), as well as the rate
constants for distribution (α) and elimination (β).
B. Extravascular administration: The
three rate constants in this
model that describe changes in plasma drug concentration
during extravascular administration are Ka (absorption), α
(distribution), and β (elimination).
48 Asha et al.
11.1.3 ThreeCompartment Open Model
11.2 Noncompartmental
Models/Noncompartmental
Analysis
The three-compartment open model provides the best explanation
for the pharmacokinetics of medications that undergo redistribution or have a strong affinity for particular tissues. Three compartments make up the body in this model: two peripheral
compartments, one containing moderately perfused tissues (like
muscles and skin) and the other containing poorly perfused tissues
(like bone, teeth, fat, and hair). The central compartment contains
the plasma and highly perfused organs. The drug first spreads
swiftly into the central compartment following an intravenous
bolus injection, then more slowly into the tissues with moderate
perfusion, and finally very slowly into the tissues with poor perfusion. A triexponential curve appears when the plasma
concentration-time profile is displayed.
Another technique for examining the duration of drug exposure in
the body without supposing a particular compartmental model is
non-compartment analysis. It uses simple algebraic equations to
compute pharmacokinetic parameters and treats the drug
concentration–time profile in plasma as a statistical distribution.
This method does not call for in-depth analyses of drug disposition.
The fact that it frequently concentrates on averages and provides
little information about the entire plasma drug concentration–time
profile is a disadvantage.
11.3 Physiological Models
Perfusion rate-limited models, another name for physiological
models, are a more recent method of examining how drugs behave
in the body. This approach treats each target site and major organ
system as a separate physiological compartment with its own tissue
volume, blood flow, drug affinity (partition coefficient), uptake
mechanism, and elimination process. Drug kinetics are expressed
in terms of flow-related equations that combine experimental estimates (such as tissue-to-plasma partition coefficients) with known
physiological data (such as organ volume and blood flow) (Fig.
These models provide a more accurate representation of medication distribution in different organs since they are grounded in
actual anatomical and physiological data. They can also predict
species differences based on perfusion rates and enable the evaluation of how physiological changes (e.g., aging) or diseases affect
medication disposition. The main disadvantage is that it takes a lot
of work to collect the required experimental data.
12 Determinants of Pharmacokinetics
12.1 Absorption
12.1.1 Bioavailability
The percentage (F) of a medicine that, following delivery, enters
the bloodstream in its unaltered chemical state is known as its
bioavailability. A drug’s bioavailability is 100% (F = 1) when administered intravenously, and it is typically very nearly 100% when
4).