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Fundamentals of Pharmacokinetics and Drug Delivery 49
Fig. 4 An illustration of a physiologically grounded pharmacokinetic model that incorporates the kidney, liver,
gut, brain, and other tissues. The organ is indicated by the subscript and the word Q denotes the blood flow
administered intramuscularly or subcutaneously. The bioavailability
of medications taken orally can range from 0% to 100%, contingent
on the extent of absorption and the influence of first-pass metabolism. Oral medications that are slowly absorbed or have limited
water solubility frequently have poor bioavailability. Additionally,
drugs with a high first-pass metabolism typically have a limited
bioavailability. For this reason, the word “bioavailability“is mo
pertinent when referring to
other routes. It’s regarded as an absolute measurement [
oral delivery than when referring to
12].
re
By comparing the area under the plasma concentration–time
curve (AUC) following oral or other non-vascular delivery with the
AUC following intravenous (IV) treatment, which signifies 100%
bioavailability (F = 1), one can ascertain absolute bioavailability.
Bioavailability oralð Þ= AUC
F = AUC
oral
=AUC
IV
× 100=AUC
oral
or
IV
100% is the bioavailability if both AUCs are equal. This metric
aids in the prediction of medication efficacy for various dosage
forms or methods of administration. Parenteral > oral > topical is
normally the sequence in which bioavailability occurs. Drug
absorption-related factors also impact the drug’s bioavailability.
Relative bioavailability F
stands for relative bioavailability, which
is the systemic availability of a medicine’s formulation compared to
an oral standard of the same drug.
50 Asha et al.
12.1.2 Bioequivalence
12.1.3 Area Under Curve (AUC)
12.2 Distribution
12.2.1 Volume of Distribution
When two identical medications or distinct formulations achieve
their peak blood concentrations simultaneously and have comparable bioavailability, this is known as bioequivalency. This indicates
that when given in the same dosage range, they result in comparable therapeutic and side effects since they produce equivalent drug
concentrations in plasma and tissues. The medications or formulations are deemed bioinequivalent if there is a notable variation in
their bioavailability.
The entire area under the plasma drug concentration–time curve,
or area under the curve (AUC), shows how much of the drug enters
the systemic circulation overall after injection. It is a crucial metric
for evaluating a medication’s bioavailability, which indicates the
degree of absorption, and it is also used to compute different
pharmacokinetic parameters. The formula for calculating the
AUC is time multiplied by drug concentration (μg/ml × hours).
Assuming the body functions as a single, uniform compartment for
the drug, the volume of distribution (Va) is the fictitious volume of
bodily fluid required to distribute the entire supplied drug to
obtain the observed plasma concentration.
Volume of distribution Vð Þ
= Amount of drug in body=Plasma drug concentration
= Dose Dð Þ =C
12.3 Elimination
12.3.1 Half-Life (t½)
Elimination half-life, or half-life (t½), is the amount of time needed
for the drug concentration in plasma to drop by 50%. It happens
during the elimination phase and has an inverse relationship with
the elimination rate constant (ẞ), i.e., a shorter half-life is obtained
with faster elimination. It is stated in minutes or hours. It is determined mathematically as follows:
Half - life t
The natural logarithm
1
2
2=β = 0:693=β
= In
of two is represented as 0.693 in the
equation. The B phase slope of the plasma drug concentration–time
curve can be used to calculate a medication’s half-life. Furthermore,
a certain formula can be used to determine the elimination half-life
using clearance (Cl) and apparent volume of distribution (V
Half - l
A dr
ug’s half-life is a measure of how long it takes to take effect
ife t
1
= 0:639:V
2
d
=CI
).
d
and is directly related to how much of it is present at the site of
action. A shorter half-life corresponds to a reduced concentration at
the target site and a shorter duration. Setting dosage intervals and
Fundamentals of Pharmacokinetics and Drug Delivery 51
figuring out how long it takes to achieve steady state at a constant
dose depend on it. Drugs with first-order kinetics have a doseindependent half-life, meaning that 95% of the drug is gone after
around 5 half-lives. On the other hand, the half-life of medications
with zero-order kinetics rises with dosage.
12.3.2 Clearance (Cl) or Body Clearance
Body clearance, often known as clearance (Cl), is the amount of
plasma that a medication is theoretically entirely cleared from in a
certain amount of time. It can be adjusted for body weight
(ml/kg/min) and is measured in volume per time (ml/min). The
relationship between clearance and the rate of removal of a plasma
medication is as follows:
Body Clearance
= Rate of Elimination=Plasma Drug Concentration
It is also calculated as the product of the apparent volume of
distribution (Vd) and the overall elimination rate constant (β):
Body Clearance = 0:693 × V
1=2
=t
d
The half-life of the drug is inversely correlated with clearance;
that is, as clearance rises, the half-life falls. Nevertheless, as clearance
also depends on the volume of distribution and elimination rate, a
short half-life does not always imply good clearance. Compared to
half-life, clearance is a more accurate indicator of elimination efficiency because it captures the rate at which drugs are removed from
the body without regard to distribution kinetics. It doesn’t say how
long a medicine stays in the body.
13 Conclusion
A vital framework for comprehending the dynamic processes of
medication absorption, distribution, metabolism, and excretion in
a variety of animal species is provided by pharmacokinetics. A
thorough comprehension is necessary to ensure therapeutic efficacy, minimize toxicity, and optimize dosage precisely. In order to
prevent medication residues in the food chain, pharmacokinetic
concepts are essential for forecasting drug interactions, food–drug
interact
and withdrawal periods in food-producing animals.
ions,
The foundation of sensible drug development, dosage formulation,
and therapeutic monitoring is compartmental pharmacokinetic
modeling. In order to improve animal health outcomes, advance
evidence-based veterinary practices, and support the safe use of
medications in a variety of species, pharmacokinetics is essential.
52 Asha et al.
References
1. Adams HR (2001) Veterinary pharmacology
and therapeutics, 8th edn. Iowa State University Press, Iowa
2. Baggot JD (1977) Principles of drug disposition in domestic animals. W. B. Saunders,
Philadelphia
3. Booth NH, McDonald LE (1982) John’s veterinary pharmacology and therapeutics, 5th
edn. Iowa State University Press, Iowa
4. Brahmanker DM, Jaiswal SB (1995) Biopharmaceutics and pharmacokinetics: a treatise.
Vallabh Prakashan, Delhi
5. Goodman LS, Limbird LE, Milnoff PB, Gilman AG, Hardman JG (1996) Goodman &
Gilman’s: the pharmacological basis of therapeutics, 9th edn. McGraw-Hill, New York
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Goodman & Gilman’s: The pharmacological
basis of therapeutics, 10th edn. McGraw-Hill,
New York
7. Lin JH, Lu AYH (1997) The role of pharmacokinetics and metabolism in drug discovery
and development. Pharmacol Rev 49:403–449
8. Lindup WE, Orme MC (1981) Plasma protein
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9. Lynch T, Price A (2007) The effect of cytochrome P450 metabolism on drug response,
interactions and adverse effects. Am Fam Phys
76(3):391–396
10. Martin RJ, Hsu WH (2008) Principles of drug
absorption, disposition and action. In: Hsu
WH (ed) Handbook of veterinary pharmacology. Wiley Blackwell, Ames
11. Martin-Jimenez T, Riviere JE (1998) Population pharmacokinetics in veterinary medicine:
potential use for therapeutic drug monitoring
and prediction of tissue residues. J Vet Pharmacol Ther 21(3):167–189
12. Riviere JE (2009) Veterinary pharmacology
and therapeutics, 9th edn. WileyBlackwell, Iowa
13. Riviere JE (2018) Handbook of comparative
pharmacokinetics and residues of veterinary
antimicrobials. CRC Press
14. Toutain PL, Del Castillo JR, Bousquet-Melou
A (2002) The pharmacokinetic–pharmacodynamic approach to a rational dosage regimen
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15. Tripathi
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KD (2008) Essentials of medical phar-
Chapter 3
Targeted Drug Delivery: Principles and Strategies
Meemansha Sharma, Mamta Meena, Ayushi Vaidhya,
and Thakur Uttam Singh
Abstract
This chapter discusses the evolving field of targeted drug delivery systems (TDDS) and drug delivery
systems (DDS) focusing on strategies to enhance the solubility and targeted delivery of insoluble pharmaceutical compounds. Various techniques are explored including changes in pH and salt development,
polymeric micelles, nanonization, liposomes, solid lipid nanoparticles, cocrystal preparation, and dendrimers. These strategies aim to overcome challenges such as poor solubility, rapid clearance, and limited
bioavailability of drugs, ultimately improving therapeutic efficacy while reducing adverse effects. Additionally, tissue-specific selective drug transporting methods are highlighted, emphasizing the significance of
tailored approaches for specific diseases. The chapter concludes by underscoring the significance of
continued advancements in technologies related to drug delivery and their potential for novel therapeutic
applications, as well as the significance of understanding receptor-ligand biology in translating targeted
systems into clinical practice. Overall, the chapter provides a comprehensive overview of existing tactics and
potential future prospects in the area of pharmaceuticals delivery, emphasizing the need for precision
medicine approaches to improve patient outcomes.
Key words Targeted drug delivery, Principles, Strategies
1 Introduction
A targeted drug delivery system (TDDS) encompasses a range of
techniques involving physicochemical methods that regulate the
supply and release of pharmacologically active compounds into
the biological systems. These active ingredients can more effectively
produce the desired effects by utilizing targeted technologies of
drug delivery [
delivery methods and formulations that optimize clinical effects
whereas reducing adverse effects [2]. The study of drug transportation is expanding in the sphere of pharmacological science [
contrast to conventional DDSs, which rely on drugs being
absorbed through biological membranes, TDDS get area-specific
release of pharmaceuticals from a dosage formulation [
1]. Drug delivery tactics addresses the effective drug
3]. In
4]. The goal
53
54 Meemansha Sharma et al.
of TDD is to regulate and control the dynamics and kinetics,
immunogenicity, biorecognition, and a specific toxicity of pharmaceuticals. The targeting of drugs may be accomplished through
various methods such as enzyme mediation, pH-dependent release,
and employing specialized carriers [
DDSs, nanoparticles have shown a great deal of promise. Now, it is
possible to encapsulate the pharmaceuticals in a variety of nanoparticle shapes, such as dendrimers, micelles, liposomes, and solid lipid
nanocarriers, to increase therapeutic efficacy and decrease unpleasant side effects [
a
chance
ceutical producing response to particular stimulus like level of pH,
heat, light or proteases and function with improved therapeutic
effect [
targeting and a review of various strategies related to insoluble
drug and tissue specific drug delivery will be discussed in detail.
for
6]. In this chapter, the fundamental principles of drug
6]
regulated drug release, giving enough time to pharma-
2 Principles of Targeted Drug Delivery
TDD is a treatment approach designed to minimize exposure to
healthy tissues while administering medication to a specified target
site within the body [7]. The fundamental idea behind drug aimed
at specific target is to minimize the presence of drug in unintended
areas while ensuring a concentrated delivery to the desired target
8]. This approach aims to diminish adverse effects stemming from
[
dispersed concentrations in non-targeted regions, allowing for elevated doses, in addition to mitigating interactions with multiple
targets. By doing so, this concept optimizes the therapeutic impact
of the medication [
unwanted interactions between the medication and biological factors within the body, affecting drug distribution to particular anatomical sites, as shown in Fig.
blood circulation, tissue structure, chemical properties, and enzymatic activity [10].
targeting necessitates the synchronized interaction of
Drug
drug, target site, and also the pharmaceutical carrier. The target
refers to particular organ, cell, or cluster of cells, whether in a
chronic/acute state requiring treatment, where the drug will act.
The carrier is a purposefully designed molecule/system crucial for
efficiently transporting the drug payload to predetermined locations [
possess several characteristics: it should be non-toxic, non-immunogenic, chemically inert, capable of degradation over time, compatible with biological systems, and maintain stability both within
the body and in laboratory settings. Additionally, it should demonstrate a pattern of drug release that is predictable and can be
controlled, be straightforward and consistent in its preparation,
11]. Ideally, a medication aimed at specific target should
5]. As transporters in present
. With nanoparticle-based drug delivery, there is
9]
urthermore, targeting diminishes
. F
1. These biological factors encompass
Targeted Drug Delivery: Principles and Strategies 55
Fig. 1 The fundamental principles of targeted drug delivery
cost-effective, easily removed from body, and minimize drug seepage while transportation [
The production of targeted pharmaceutics should consider the
special qualities of target cells, additionally the features of the
transport carriers/vehicles in charge of delivering drug to certain
receptors to guarantee that these ideal qualities can be attained
13]. These significant factors encompass the drug concentration,
[
location and spread of particles, molecular size, chemical properties, enzymatic activity, electric field, physiological conditions, type
and also number of polymers or excipients, and the surface characteristics (including shape, charge, size, and density) of the carrier
system. To achieve effective targeting of specific cells or tissues, it’s
crucial to manage physiological factors like blood circulation during intravenous drug administration and tissue structure, as well as
physicochemical aspects such as the shape, binding strength, composition, and modification of carrier [
the enhanced permeability and retention (EPR) effect in medical
environments, extravasation, distribution within tumors, tumor
variability, and the presence of overexpressed markers play pivotal
roles in ensuring the effectiveness of treatments targeting
tumors [
15].
If the
desired characteristics are adequately achieved and additionally the formulation aspects are carefully addressed, TDD holds
significant promise in advancing nanomedicine and therapeutic
interventions. While TDD of fers potential benefits for managing
various chronic as well as infectious illnesses, its most critical application lies in combating cancerous tumors. This is primarily because
of its improved ability to penetrate tumor microenvironments and
12].
14]
oreover, factors like
. M
56 Meemansha Sharma et al.
achieve higher drug concentrations at specific site of
malignancy [
The potential applications and objectives of TDD encompass a
wide range of fields including cancer treatment, vaccine enhancement, delivery to the ocular segment, brain regions, transportation
of DNA and oligonucleotides, TDD within cells and throughout
the body, oral and topical administration routes, utilization in
enzyme immunoassays, in addition to radioimaging [
bly, the reported outcomes associated with these applications often
involve decreased toxicity, enhanced cellular uptake, prolonged
circulation within systemic circulation leading to enhanced drug
availability, augmented immune responses, enhanced drug absorption and penetration, also drug retention time improved in the
body [
16].
17–19]. Nota-
20].
3 Strategies Related to Site Specific Delivery of Insoluble Pharmaceutical
Compounds
Oral medications can be swiftly cleared from the body due to
factors including stomach hydrolysis, enzymatic breakdown in gastric and small intestinal fluids, degradation in gut wall, and liver
metabolism before systemic circulation [
ceutical development is often to enhance the dispersion of a waterinsoluble pharmaceutical molecule in the gastrointestinal tract in
order to attain adequate bioavailability when taken by mouth
22]. The following section discusses the most common methods
[
used to increase the solubility of medications with limited water
solubility (Fig.
2).
21]. The goal of pharma-
3.1 Changes in pH and Salt Development
The majority of medicines are slightly basic, and about 70% of
pharmaceuticals are ionizable [
have a pH-dependent solubility; weakly basic drugs are soluble at
pH > pKa, while slightly acidic compounds easily dissolve at
pH < pKa [
utilized to manufacture limited water-soluble drugs [
floxacin is a traditional medication that has a weak basicity and is
almost undissolved in fluids at neutral pH. Nevertheless, it shows
that its solubility is pH-sensitive, becoming more soluble in acidic
conditions [
basic medications offers an additional method for formulating
drugs with pH-dependent solubility [
accepted opposing ions in these salts can create favorable pH levels
upon dissolution in water, resulting in a solution with a pH close to
the maximum solubility pH of the drugs [
forms may eliminate the requirements for pH modification which
are essential for solubilizing the drugs. Furthermore, formation of
salt has been observed to enhance crystalline structure, strength,
24]. This pH-dependent solubility has been extensively
Alternatively, making salts out of mildly acidic or
25].
23]. Ionizable pharmaceuticals
24]. Cipro-
26]. Pharmaceutically
26]. Consequently, salt
Targeted Drug Delivery: Principles and Strategies 57
Fig. 2 The forms of targeted drug delivery of poorly soluble compounds
3.2 P
Micelles
olymeric
and the pharmaceutical processability of drugs [ 27]. The market
offers rosuvastatin (partially soluble) in the form of its calcium salt
[
25]. Phar maceutical industries are always investigating medication
salt formulations in an effort to improve clinical efficacy [
28]. Occa-
sionally, it appears that pharmaceutical firms are using reformulation as a different way to take advantage of marketing access and
captives.
Amphiphilic block copolymers create microscopic shell structures
known as polymeric micelles. Micelles polymers are very well suited
for drug administration due to their inherent and adjustable characteristics [
29]. Encapsulating water-insoluble drugs in micelles
allows them to be formulated in aqueous vehicles due to their
affinity for hydrophobic solvents because of their inclination toward
non-polar liquids and the hydrophobic regions of micelles, facilitated by hydrophobic-hydrophobic interactions [
22].
Diblock
polymers like PEG-PLA (polyethylene glycol-poly lactic acid) or
polymers of triblock PEG-(PLA-PLA) are utilized to generate
polymeric micelles [
30]. In a polymer for micelles (Fig. 3), the
PEG is typically the polar component, while the tail of hydrophobic
component can consist of polylactic acid, polyaspartic acid, polycaprolactic acid [
25]. Moreover, polymeric micelles can be engi-
neered for active targeting with the use of site-specific compounds
and pH-responsive release of drug at particular tissues. Paclitaxel is
contained in micelles of polymeric nature called Genexol-PM,
31].
which are made of PEG polymer [
This has been the initial
58 Meemansha Sharma et al.
Fig. 3 Polymeric micelles (therapeutic agent—pink color)
version of first FDA-approved formulation of polymeric micelles,
and it is said to be more secure and tolerable than other commercial
formulations [31]. Additionally, micellar solubilization has been
effective in the development and commercialization of numerous
medications with low water solubility, including paclitaxel injection, cyclosporine injection, and griseofulvin-PEG-dispersion [
22].
3.3 N
anonization
The technique of using active medication as sub-micron-sized particulates, or nanoparticles, is called nanonization [
32]. Within the
drug sectors, formulations of size lesser than 1 μm are defined as
nanoparticles [32]. Different methods, generally classified as “bottom up” and “top down” technologies, may be utilized to produce
drug nanoparticles [
33]. Reducing the dimension of the medica-
tion to the nanometer scale enhanced its surface area, which can
potentially boost its diffusion rate [34]. This is the basic basis of the
process of nanonization for hydrophobic medications. The large
surface area of nanoparticles facilitates their easy solubility in
liquids, which enhances dissolution of the included medications
[
The process of the micronization has been extensively
34].
researched, but size reduction to the nanoscale can speed up the
material’s solubility and enhance its rate of dissolution. Nanostructured medicines can achieve distinctive surface properties through
processes like functionalization and coating with specific molecules.
These molecules include elongated hydrophilic co-polymers like
polyethylene glycols and polyethyleneimine, along with molecules
that bind to receptors like folic acid, carbohydrates, oestradiol, and
monoclonal antibodies. These modifications enhance the
medicine-targeting abilities, improve its stability, and optimize its
interaction with biological systems, thus advancing its therapeutic
These changes enhance the precision of pharmaceuti-
efficacy [
35].
cal delivery by enabling selective targeting to cells that have overexpressed receptors.