LET’S BEGIN!

UNIT 1 -Week (1-3): Introduction to General Toxicology

Intended Learning Outcomes (ILO)

At the end of the unit, you are expected to:

1. Describe the basic of concept of toxicology.

2. Differentiate the various areas of toxicology

3. Determine toxicological hazards and risk.

Introduction
Luisetto (2016) mentioned that Poisoning is a rare event often, but in some
cases whit critical consequences and so the right diagnosis and therapy is a golden
endpoint. The toxicology medical equip must be multi-professional. Antidotes are
used not often but rarely, and physicians need rapid information also in medicinal
chemistry and toxicology field. The management of the systems must involve
clinical and logistic pharmacist.

This unit will focus on the definitions of toxicology and any other terms related.
It also deals with the history of toxicology and its various fields of practice. Please
proceed immediately to the “Unlocking of Difficulties” part since the first lesson is
also definition of essential terms.

Unlocking of Difficulties

To attend the following intended learning outcomes for the first lesson of
the course, you need to fully understand the following essential knowledge that
will be laid down in the succeeding pages. Please note that you are not limited to
exclusively refer to these resources. Thus, you are expected to utilize other books,
research articles and other resources such as e-journals and various pharmacy
mobile applications.

Key Terms:

▪ TOXICOLOGY- is the study of the adverse effects of xenobiotics

on living systems.
 ▪ XENOBIOTICS- is a term used to describe chemical substances that are
foreign to animal life and thus includes such examples as plant constituents,
drugs, pesticides, cosmetics, flavorings, fragrances, food additives, industrial
chemicals and environmental pollutants..

▪ HAZARD- is any source of potential damage, harm or adverse health effects

on something or someone.

▪ RISK- is the chance or probability that a person will be harmed or experience

an adverse health effect if exposed to a hazard. It may also apply to
situations with property or equipment loss, or harmful effects on the
environment.

Lecture Notes

Do you have any idea on the development of antidotes and discovery of

poisons? Let`s find out the people behind in the discovery of our antidotes in the
modern era.

I. HISTORY & SCOPE OF TOXICOLOGY

A. ANTIQUITY
➢ Knowledge of animal venoms and plant extracts or hunting, warfare,
and assassination presumably predate recorded history.

▪ PAPYRUS EBERS- contains information of many recognized poisons such as

hemlock, aconite, opium, metals such as lead, copper and antimony.

Figure 1: Papyrus Eber

(BMJ Publishing Group Ltd., 2020)
▪ BOOK OF JOB- poison arrows
 “For the arrows of the Almighty are within me, the poison whereof drinketh
up my spirit: the terrors of God do set themselves in array against me”.
~Job 6:4~

▪ HIPPOCRATES- Toxicology principles on bioavailability in therapy &

overdosage.

Figure 2: Hippocrates
(Hektoen International Journal, 2021)

▪ THEOPHRASTUS-reference of poisonous plants in Historia plantarum.

Figure 3: Theophrastus
(Science Photo Library Limited, 2021)

▪ DIOSCORIDES- 1st attempt of classifying poisons as plant, animal &

mineral.
 Figure 4: Dioscorides
(Science Photo Library Limited, 2021)

▪ KING MITHRIDATES VI OF PONTUS- Antidote concoction, he regularly

ingested mixture of 36 ingredients as protection against assassination.

Figure 5: King Mithridates

(Ancient Origins, 2021)

▪ Lucius Cornelius Sulla - issued “Lex Cornelia”, the 1st law against
poisoning.
 Figure 6: Sulla
(March Calender, 2014)

▪ MAIMONIDES- Treatise on poisons and their treatment from insects,

snakes, and mad Dogs in middle ages.

Figure 7: Maimonides
(Lapham`s Quarterly, 2021)

▪ CATHERINE DE MEDICI- tested toxic concoctions w/c includes the toxic

response (ONSET OF ACTION), the effectiveness of the compound
(POTENCY), the Degree of response of the parts of the body (SPECIFICITY &
SITE OF ACTION), and the complaints of the victim (CLINICAL SIGNS AND
SYMPTOMS).
 Figure 8: CATHERINE DE MEDICI
(http://zeebaishkanwal116.blogspot.com/2017/12/king-louis-xiv.html)

▪ PARACELSUS (1493-1541)
➢ Philippus Aureolus Theophrastus Bombastus Von Hohenheim-
Paracelsus
➢ “All substances are poisons: There is none which is not a poison. The
right dose differentiates a poison from a remedy”.
➢ Father of Toxicology in Renaissance period.
➢ Physician- alchemist, formulate many revolutionary views that
remain integral to the structure of toxicology, pharmacology, and
therapeutics.
➢ He focused on the primary toxic gent as chemical entity
➢ He stated that:
1. Experimentation is essential in the examination of responses
to chemicals
2. One should make distinction between the therapeutic and
toxic properties of chemicals
3. These properties are sometimes but not always in
indistinguishable, except by dose
4. One can ascertain in degree of specificity of chemicals and
their therapeutic or toxic effects.
 Figure 9: Paracelsus
(Britannica, 2020)

▪ Mathieu Joseph Bonaventure Orfila

➢ “father of modern toxicology” in the Age of Enlightenment
➢ his interest centered on harmful effects of chemicals as well as
therapy of chemical effects.
➢ he introduced quantitative methodology into the study of the
actions of chemicals on animals.
➢ valuable use of chemical analyses for proof that existing
symptomatology was related to the presence of the chemical in the
body.

Figure 10: Orfila

(Science Source, 2020)
 ▪ FRANÇOIS MAGENDIE
➢ Studied the mechanisms of action of emetine and strychnine.

Figure 11: Magendie

(American Association of Neurological Surgeons, 2021)
▪ LOUIS LEWIN
➢ published much of the early work on the toxicity of narcotics,
methanol, glycerol, acrolein, and chloroform.

Figure 12: Lewin

(Toxipedia, 2018)

II. DIFFERENT AREAS OF TOXICOLOGY

1. Mechanistic Toxicology
➢ Identifies the cellular, biochemical, and molecular mechanism by
which chemicals exert toxic effects on living organisms.

Figure 13: Mechanistic Toxicology

(https://toxicology.tamu.edu/program/research-areas/mechanistic-toxicology/)
2. Descriptive Toxicology
 ➢ Concerned directly with toxicity testing, which provides information
or safety evaluation and regulatory requirements.

Figure 14: Descriptive Toxicology

(The Scientist, 2021)

3. Regulatory Toxicology
➢ has the responsibility or deciding, on the basis of data provided by
descriptive and mechanistic toxicologists, whether a drug or another
chemical poses a sufficiently low risk to be marketed or a stated
purposes.

Figure 15: Regulatory Toxicology

(Charles River Laboratories, 2021)

4. Forensic Toxicology
➢ is a hybrid of analytic chemistry and fundamental toxicologic
principles that focuses primarily on the medicolegal aspects of the
harmful effects of chemicals on humans and animals.

Figure 16: Forensic Toxicology

(Labcompare, 2021)
5. Toxicogenomics- permits the application of genomic, transcriptomic,
proteomic, and metabolomics technologies to identify descriptive and
mechanistic information that can protect genetically susceptible individuals.

Figure 17: Toxicogenomics

(Springer Nature Switzerland AG., 2021)

6. Clinical Toxicology - is concerned with disease caused by or

uniquely associated with toxic substances.

Figure 18: Clinical Toxicology

(Emergency Pedia, 2021)

7. Environmental Toxicology- focuses on the impacts of chemical

Pollutants in the environment on biological organisms, specifically studying the
impacts of chemicals on nonhuman organisms such as fish, birds, terrestrial
animals, and plants.

Figure 19: Environmental Toxicology

(University of Bergen, 2021)
8. Developmental toxicology
 ➢ is the study of adverse effects on the developing organism that may
result from exposure to chemical or physical agents be before
conception (either parent), during prenatal development, or
postnatally until the time of puberty.

9. Reproductive toxicology
➢ is the study of the occurrence of adverse effects on the male or
female reproductive system that may result from exposure to
chemical or physical agents.

Figure 20: Developmental & Reproductive Toxicology

(National Institute of Environmental Health Sciences, 2021)

III. TOXICOLOGICAL TERMS

▪ Toxicity- the ability of a chemical agent to cause injury. The injuries occur
depends on the amount of chemical absorbed.

▪ Hazard – the likelihood that injury will occur in a given situation or setting;
the condition of use and exposure are primary consideration.

▪ Risk – the expected frequency of the occurrence of an undesirable effect

arising from exposure to a chemical or physical agent.

▪ Poison – any substance applied to the body, ingested, inhaled or

developed within the body which causes or may cause damage or
disturbance of function.

▪ Treatment – is the management and care of a patient or the overcoming or

combating of a disorder.
 ▪ Symptom – any evidence of disease or of a patient’s condition, a change in
a patient’s condition indicative of some bodily or mental state.

▪ Poisoning – is a morbid condition produced by a poison.

▪ Posology – treats of the form and quantity of medicine to be administered

at one time or within a certain period.

▪ Dose – is the quantity of medicine to be administered at one time or within

a certain period, usually one day.

▪ Minimum dose – the smallest amount which produces therapeutic effects

or beneficial action upon the sick.

▪ Average dose or Customary dose – the dose which may be expected

ordinarily to produce the therapeutic effects for which the preparation is
employed.

▪ Maximum dose – is the largest amount which can be safely used in

ordinary cases.

▪ Toxic dose or Poisonous dose – is the dose that is harmful to both the
healthy and the sick, but is not fatal.

▪ Lethal or Fatal Dose – is the dose which kills or is the dose which is just
sufficient to cause death.

▪ LD – Lethal dose

▪ MLD – Minimum Lethal dose

▪ LD50 – the amount (dose) which kills 50% of a group of test animals
(usually 10 or more) or tested on 50 animals.

▪ LD100 – the amount (dose) which kills 100% of a group of test animals
(usually 10 or more) or tested on 100 animals.

▪ Margin of safety – the magnitude of the range of doses involved in

progressing from a non-effective dose to a lethal dose.

IV. SPECTRUM OF UNDESIRED EFFECTS

▪ In therapeutics, e.g., each drug produces a number of effects but usually
only one effect is associated with the primary objective of the therapy; all
the other effects are referred to as undesirable or side effects.
▪ Allergic Reactions
➢ is an immunologically mediated adverse reaction to a chemical
resulting from previous sensitization to that chemical or to a
structurally similar one.

Figure 21: Allergic Reactions

(Palm Bay Urgent Care, 2020)
▪ Idiosyncratic Reactions
➢ refers to a genetically determined abnormal reactivity to a chemical.
➢ the response observed is usually qualitatively similar to that
observed in all individuals but may take the form of extreme
sensitivity to low doses or extreme insensitivity to high doses of the
chemical.
➢ EXAMPLE: patients who exhibit prolonged muscular relaxation and
apnea (inability to breathe) lasting several hours after a standard
dose of succinylcholine.

▪ Reversible versus Irreversible Toxic Effects

➢ The ability of that tissue to regenerate largely determines whether
the effect is reversible or irreversible.
➢ Thus, for a tissue such as liver, which has a high ability to regenerate,
most injuries are reversible, whereas injury to the CNS is largely
irreversible because differentiated cells of the CNS cannot divide and
be replaced.

▪ Immediate versus Delayed Toxicity

➢ Immediate toxic effects can be defined as those that occur or
develop rapidly after a single administration of a substance.
 ➢ Whereas delayed toxic effects are those that occur after the lapse of
some time.

▪ Local versus Systemic Toxicity

➢ Local effects are those that occur at the site of first contact between
the biological system and the toxicant.
➢ Systemic effects require absorption and distribution of a toxicant
from its entry point to a distant site, at which deleterious effects are
produced.

▪ Tolerance
➢ is a state o decreased responsiveness to a toxic effect of a chemical
resulting from prior exposure to that chemical or to a structurally
related chemical.

➢ Two major mechanisms are responsible for tolerance:

1. Due to a decreased amount of toxicant reaching the site
where the toxic effect is produced (dispositional tolerance)
2. Due to a reduced responsiveness of a tissue to the
chemical.

▪ SELECTIVE TOXICITY- that a chemical produces injury to one kind of living

matter without harming another form or life even though the two may
exist in intimate contact.

▪ The individual or “graded” dose–response relationship- describes the

response of an individual organism to varying doses of a chemical.

▪ A Quantal dose response relationship- characterizes the distribution of

responses to different doses in a population of individual organisms.

▪ Hormesis- a “U-shaped” dose–response curve, results with some

xenobiotics that impart beneficial or stimulatory effects at low doses but
adverse effects at higher doses.
 Figure 22: Hormesis
(Science Direct, 2021)

▪ THERAPEUTIC INDEX
➢ is defined as the ratio of the dose required to produce a toxic effect
and the dose needed to elicit the desired therapeutic response.
➢ used to compare the therapeutically effective dose to the toxic dose
of a pharmaceutical agent.
➢ The common method used to derive the TI is to use the 50% dose-
response points, including TD50 (toxic dose) and ED50 (effective
dose).

Figure 23: Therapeutic Index

(Wiley Online Library, 2021)

➢ For example, if the TD50 is 200 and the ED50 is 20 mg, the TI would
be 10.
 Figure 24: Comparison of Therapeutic Index of two drugs
(U.S. National Library of Medicine, 2021)

➢ In figure 24, a clinician would consider a drug safer if it had a TI of 10

than if it had a TI of 3.
➢ A higher value on the Therapeutic Index indicates a more favorable
safety profile.
➢ However, the use of the ED50 and TD50 doses to derive the TI may
be misleading about a drug's safety, depending on the slope of the
dose-response curves for therapeutic and toxic effects.
➢ To overcome this deficiency, toxicologists often use another term to
denote the safety of a drug: the Margin of Safety.

▪ Margin of Safety
➢ The Margin of Safety (MOS) is usually calculated as the ratio of the
toxic dose to 1% of the population (TD01) to the dose that is 99%
effective to the population (ED99).
Formula:
MOS=TD01
ED99

Figure 25: Relationship between effective dose response and toxic

dose response
(U.S. National Library of Medicine, 2021)
 ➢ In figure 25, shows the relationship between effective dose response
and toxic dose response. T
➢ The shaded area represents the doses at which the substance
produces an effective dose response while the toxic dose response
remains below the TD50.
➢ The slope of a curve shows how dose increases result in responses to
the effective or toxic dose.
➢ Because of differences in slopes and threshold doses, low doses may
be effective without producing toxicity.
➢ Although more patients may benefit from higher doses, that is
offset by the probability that toxicity will occur.

▪ No Observed Adverse Effect Level (NOAEL)

➢ Highest dose at which there was not an observed toxic or adverse
effect.
▪ Lowest Observed Adverse Effect Level (LOAEL)
➢ Lowest dose at which there was an observed toxic or adverse effect.

Figure 26: A dose-response curve showing doses where the NOAEL and LOAEL
occur for a substance
(U.S. National Library of Medicine, 2021)

➢ In figure 26, shows a dose-response curve where the NOAEL occurs

at 10 mg and the LOAEL occurs at 18 mg.
➢ Sometimes the terms No Observed Effect Level (NOEL) and Lowest
Observed Effect Level (LOEL) are also used.
➢ NOELs and LOELs do not necessarily imply toxic or harmful effects
and can be used to describe beneficial effects of substances.
➢ The NOAEL, LOAEL, NOEL, and LOEL are commonly used in risk
assessments and research.
V. ROUTES & DURATION OF EXPOSURE
Industrial setting:
▪ Inhalation – major route of entry

Figure 27: Inhalation Route

(Levitt-Safety Ltd, 2021)
Others:
▪ Transdermal route
▪ Oral ingestion – for pollutants of water and soil; as the principal route of
exposure for humans.

Figure 28: Transdermal Route

(MSD Manual, 2021)

▪ Acute exposure – single or multiple exposure occurring 1 to 2 days.

▪ Chronic exposure – multiple exposures continuing over a longer period of
time; repetitive exposure.
▪ Low-level long-term exposure – contact with small conc. of chemicals over
long period of time.
▪ Delayed Toxicity – the appearance of toxic effect after a variable interval.

Focus Questions
Guide questions for Unit 1 discussions:
1. Why toxicology is essential in the field of pharmacy practice?
2. As a future pharmacist, how will you educate the public in handling drug toxicity?

Related Readings
Related readings will be posted via schoology to supplement the foundation of
the topics discussed in Unit 1 module.

Learning / Assessment Activities

Learning assessment will be served as your assignment and quiz and will be given
via schoology at the end of the week after our virtual consultation.
UNIT 2 -Week (4-5): Mechanisms of Toxicity & Toxicokinetics
Intended Learning Outcomes (ILO)

At the end of the unit, you are expected to:

1. Describe the mechanism of toxicity of poisons.

2. Determine the toxicokinetics of poisons.

3. Describe the primary routes of exposure and their effect on

toxicant absorption and distribution.

Introduction
Gupta (2016) stated that toxicokinetics refers to the study of
absorption, distribution, metabolism/biotransformation, and excretion
(ADME) of toxicants/xenobiotics in relation to time. The basic kinetic
concepts for the absorption, distribution, metabolism, and excretion of
chemicals in the body system initially came from the study of drug actions or
pharmacology; therefore, this area of study is traditionally referred to as
pharmacokinetics.
This unit will focus on the routes and exposure of toxicants in our
body. Please proceed immediately to the “Unlocking of Difficulties” in order
to understand the terms used in the Lecture notes.

Unlocking of Difficulties

To attend the following intended learning outcomes the lesson of the

course, you need to fully understand the following essential knowledge that
will be laid down in the succeeding pages. Please note that you are not
limited to exclusively refer to these resources. Thus, you are expected to
utilize other books, research articles and other resources such as e-journals
and various pharmacy mobile applications.

Key Terms:

▪ DRUG METABOLISM- is the term used to describe the

biotransformation of pharmaceutical substances in the body so
that they can be eliminated more easily.

▪ DRUG ABSORPTION– is the process of a drug moving from its

site of delivery into the bloodstream.
1
 ▪ DRUG DISTRIBUTION- refers to the movement of a drug to and
from the blood and various tissues of the body (for example, fat,
muscle, and brain tissue) and the relative proportions of drug in
the tissues.

▪ DRUG EXCRETION- is the removal of drugs from the body, either

as a metabolite or unchanged drug.

▪ TOXICOKINETICS- encompasses rates of absorption,

distribution, metabolism (biotransformation), and excretion
(ADME) of toxicants or toxins.

Lecture Notes

Do you have any idea on how toxic substances are absorbed,

metabolized, distributed to various sites and tissues or even
how they are excreted in our body? In this unit, we will
determine the toxicokinetics of toxicants.

I. TOXICOKINETICS OF CHEMICALS
▪ Toxicity involves toxicant delivery to its target or targets and
interactions with endogenous target molecules that may trigger
perturbations in cell function and/or structure or that may initiate
repair mechanisms at the molecular, cellular, and or tissue levels.

▪ Biotransformation to harmful products is called toxication or

metabolic activation.
Example:
When methanol is metabolize into formic acid which can cause
blindness

2
 Figure 1: Toxication of methanol
(Berland, 2020)

▪ Biotransformations that eliminate the ultimate toxicant or prevent its

formation are called detoxications.
Example:
The inhibition of alcohol dehydrogenase is fundamental to the
treatment of methanol poisoning which causes metabolic acidosis,
blindness and death.

Figure 2: Detoxications of alcohol

(Massachusetts Medical Society, 2021)

▪ Apoptosis, or programmed cell death, is a tightly controlled,

organized process whereby individual cells break into small
fragments that are phagocytosed by adjacent cells or macrophages
without producing an inflammatory response.

3
 Figure 3: Apoptosis
(Online Biology Notes, 2020)

▪ Toxicokinetics
➢ refers to the quantitation of the time course of toxicants in the
body during the processes of absorption, distribution,
metabolism, and excretion (ADME) or clearance of toxicants.
➢ It is a reflection of how the body handles toxicants as indicated
by the plasma concentration of that xenobiotic at various time
points

4
 Figure 4: Toxicokinetics
(Springer Nature Switzerland, 2020)

II. FACTORS AFFECTING CHEMICAL DISPOSITION

1. If the rate of absorption is low → high concentration at the site of
action to cause toxicity is not attainable.

2. Distribution of a toxicant concentrated in a tissue other than the

target organ → Decrease toxicity

3. Biotransformation of chemical →Formation of less toxic or more

toxic metabolites at fast or slow rate.

4. The rapid eliminated chemical from an organism → the lower will be

its concentration of toxicity in target site.

III. ABSORPTION OF TOXICANTS

▪ CHEMICAL ABSORBED INTO THE BLOODSTREAM
➢ through any of the major barriers is distributed, at least to
some extent,
➢ throughout the body, including the site where it produces
damage.
➢ This site is called the target organ or target tissue.

▪ CELL MEMBRANES
➢ Toxicants usually pass through a number of cells, such as the
stratified epithelium of the skin, the thin cell layers of the lungs
or
➢ the gastrointestinal (GI) tract, capillary endothelium, and
ultimately the cells of the target organ.
➢ The basic unit of the cell membrane is a Lipid bilayer composed
primarily of phospholipids, glycolipids, and cholesterol.

▪ A toxicant may pass through a membrane by:

1. PASSIVE TRANSPORT
➢ Most toxicants cross membranes by simple diffusion, following
the principles of Fick’s law which establishes that chemicals

5
 traverse from regions of higher concentration to regions of
lower concentration without any energy expenditure.

➢ Small hydrophilic molecules (up to about 600 Da) permeate

membranes through aqueous pores in a process termed
paracellular diffusion, whereas hydrophobic molecules diffuse
across the lipid domain of membranes (transcellular
diffusion).

2. SPECIALIZE TRANSPORT
➢ Cell provides energy to translocate the toxicant across its
membrane.
➢ Some compounds are too large to pass through aqueous pores
or too insoluble in lipids to diffuse across the lipid domains of
membranes.
➢ Three Types of Specialize Transport: FACILITATED DIFFUSION,
ACTIVE TRANSPORT & XENOBIOTIC TRANSPORTER

2.1. FACILITATED DIFFUSION

➢ Carrier mediated transport that exhibits the properties of
active transport except that the substrate is not moved
against an electrochemical or concentration gradient.

2.2. ACTIVE TRANSPORT

→It is characterized by:
✓ Movement of chemicals against electrochemical or
concentration gradients

✓ Saturability at high substrate concentrations,

✓ Selectivity for certain structural features of chemicals,

✓ Competitive inhibition by chemical cogeners or compounds

that are carried by the same transporter,

✓ Requirement for expenditure of energy, so that metabolic

inhibitors block the transport process.

2.3. XENOBIOTIC TRANSPORTER

6
 ➢ Xenobiotic transporters are responsible for the uptake of
some chemicals into cells, and extremely important for the
export of chemicals out of cells.

➢ Some microsomal enzyme inducers will enhance the

plasma disappearance and biliary excretion of some
xenobiotics that are not biotransformed in the intact
animal, as well as in isolated hepatocytes.

➢ This is due to an up-regulation of xenobiotic transporters.

As a result, some microsomal enzyme inducers will enhance
the elimination and decrease the toxicity of some chemicals
by enhanced transport (Klaassen, 2002).

IV. EXCRETION & REABSORPTION OF TOXICANTS

▪ Excretion is the removal of xenobiotics from Blood and their return
to the external environment.
▪ Excretion is a physical mechanism, whereas biotransformation is a
chemical mechanism or eliminating the toxicant.
▪ Some chemicals may be excreted through:
✓ Excretion rom the mammary gland in breast milk,
✓ Excretion in bile,
✓ Excretion into the intestinal lumen from blood.
✓ Volatile, nonreactive toxicants such as gases and volatile
liquids diffuse from pulmonary capillaries into the alveoli
and are exhaled.

▪ Reabsorption of toxicants in the blood are filtered at the

glomerulus into the renal tubules.
▪ These filtered toxicants may reenter the blood by diffusing
through peritubular capillaries.
▪ This reentry is facilitated by tubular fluid reabsorption which
increases intratubular fluid concentration and residence time
of non-reabsorbed chemical by slowing urine flow.

Focus Questions

Guide questions for Unit 2 discussions:

1. What are the factors that affects the toxicokinetics of toxicants?
2. What will happened if toxicants are not easily eliminated in our body?

7
Related Readings
Related readings will be posted via schoology to supplement the
foundation of the topics discussed in Unit 2 module.

Learning / Assessment Activities

Learning assessment will be served as your assignment and quiz and will be
given via schoology at the end of the week after our virtual consultation.

References

Canadian Centre for Occupational Health & Safety retrieved last February 8,
2021 from
https://www.ccohs.ca/oshanswers/hsprograms/hazard_risk.html

Klaasen, Curtis D., Casarett and Doull’s Toxicology The Basic Science of
Poisons, Third edition, McGraw-Hill, 2015

Luisetto, M., Pharmaceutical Care and Toxicology, a Synergy in High Risk

Situation. Journal of Applied Pharmacy, 2016

Murpy, John. Clinical Pharmacokinetics, 6th Edition, 2017.