TOXICOLOGY Question and Answer bank is aimed to make the study of toxicology simple and understandable -----
Cont’d from series 10
Q. 1 Define ADME?
ADME is the study of absorption, distribution, metabolism/ biotransformation and excretion (ADME) of toxicants/ xenobiotics in relation to time.
Q.2 What is Toxicokinetics?
It refers to the study of
absorption, distribution, metabolism/ biotransformation and excretion (ADME) of toxicants/ xenobiotics in relation to time.
An important parameter in toxicokinetic is to examine the time course of blood
or plasma concentration of the toxicant with time.
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Q.3 What is dosage regimen?
Dosage regimen is defined as the
manner in which a drug is administered.
Irrespective of the route of
administration, a dosage regimen is composed of two important variables;
(i) the magnitude of each dose
(dose size), and
(ii) the frequency with which the
dose is repeated (dosing interval).
Q.4 Define in brief dose
size?
Dose or dose size is a quantitative term estimating the
amount of drug, which must be administered to produce a particular biological
response i. e. to achieve a specified target plasma drug concentration.
Q.5 How the therapeutic dose should be selected?
As the magnitude of both therapeutic and toxic responses
depends on plasma drug concentration, size of dose should be so selected that
it produces the peak plasma concentration (Cmax) or steady state
level within the limits of therapeutic range (between minimum effective
concentration and maximum safe concentration). The therapeutic plasma
concentration range is obtained by careful clinical evaluation of the response
in a sufficient number of appropriately selected individuals (for microbials,
the range is based upon the minimum inhibitory concentration for susceptible microorganisms).
Q. 6 What do you mean by
dosing interval?
Dosing interval is the time
interval between doses. It ensures maintenance of plasma concentration of a
drug within the therapeutic range for entire duration of therapy.
Q.7 What do
you mean by extravascular administration (EV)?
Administered of xenobiotic
by EV route (e.g., oral IM, Sc, IP etc.) is called EV administration (other
than IV route).
Q.8 Define minimum effective
concentration (MEC)
Minimum effective concentration
(MEC) is the minimum concentration of drug in plasma
required to produce the desirable pharmacological/therapeutic response. In case
of antimicrobials, the term minimum inhibitory concentration (MIC) is used, which may be
defined as the minimum concentration of antimicrobial agent in plasma required
to inhibit the growth of micro-organims.
Q.9 Define maximum safe concentration (MSC) or minimum toxic
concentration (MTC)
Maximum safe concentration (MSC) or minimum toxic
concentration (MTC) is the concentration
of drug in plasma above which toxic effects are produced. Concentration of drug
above MSC is said to be in toxic level. The drug concentration between MEC and
MSC represents the therapeutic range.
Q.10 Define maximum
plasma concentration/Peak plasma concentration (Cmax or Cpmax)
Maximum plasma concentration/Peak plasma concentration is the point of
maximum concentration of drug in plasma. The maximum plasma concentration
depends on administered dose and rates of absorption (absorption rate constant,
Ka) and elimination (elimination rate constant, β). The peak
represents the point of time when absorption equals elimination rate of the
drug. It is often expressed as
g/ml.
Exercise 2
Q.1 Define area under curve (AUC)
Area under curve (AUC) is the total
integrated area under the plasma drug concentration-time curve. It expresses
the total amount of drug that come into systemic circulation after
administration of the drug.
Q.2 Define peak effect
Peak effect is the maximal or peak pharmacological or toxic effect
produced by the drug. It is generally observed at peak plasma concentration.
Q.3 Define time of maximum
concentration/Time of peak concentration (tmax):
Time of maximum
concentration/ time of peak concentration is the time required
for a drug to reach peak concentration in plasma. The faster is the absorption
rate, the lower is the tmax. It is also useful in assessing efficacy
of drugs used to treat acute conditions (e.g., pain) can be treated by a single
dose. It is expressed in hours.
Q.4 Define onset of action
Onset of action is the beginning of
pharmacological or toxicological effect or
response produced by the drug. It occurs when the plasma drug
concentration just exceeds the MEC.
Q. 5 Define onset time
Onset time is the time required
for the drug to start producing pharmacological or toxic response. It usually
corresponds to the time for the plasma concentration to reach MEC after
administration of the drug.
Q.6 Define duration of
action
Duration of action is the time period for
which pharmacological or toxic response is produced by the drug. It usually
corresponds to the duration for which the plasma concentration of drug remains
above the MEC level.
Q.7 Define the term half-life
Half-life (T½) may be defined as
the time taken for the concentration of a compound/ toxicant in plasma to
decline by ½ or 50% of its initial value (or it may be defined as the time
required for the body to eliminate half of the chemical). This value is
determined during the elimination phase of a chemical; therefore, it is called
as elimination half-life.
Q.8 What are physiochemical
properties that affect absorption?
i) route
ii) duration
of exposure
iii) ability to cross cell membrane (passive and active transport,
endocytosis)
Q.9 Out of non-ionized or ionized
forms of chemicals, which form passively diffuse
Only non ionized
Q.10 What are determinants of
ionization?
a) pKa =
-log [acid dissociation constant]
b) pH of the local environmemt
b) pH of the local environmemt
Exercise 3
Q.1 What does it mean when pKa =
pH?
It means 50% ionization
Q,2 What happens to weak acids when
they are in an environment where the pH decreases?
More become non-ionized, and are
passively diffusible (example, diffuse in the stomach).
Q.3 What happens to weak basic when
they are in an environment where the pH decreases?
Becomes more non-ionized (eg:
intestine)
Q.4 What is bioavailability?
The
proportion of a drug or toxicant which enters the circulation when introduced
into the body and so is able to have an active effect.
Q.5
Name six things that affect distribution
i)
lipid/water soluble
ii) serum protein binding
iii) presence of specialized barriers
iv) degree of organ/tissue perfusion
v) presence/density of receptors/transporters
vi) tissue storage
ii) serum protein binding
iii) presence of specialized barriers
iv) degree of organ/tissue perfusion
v) presence/density of receptors/transporters
vi) tissue storage
Q.6
What is drug interactions?
Using 2 drugs at the
same time may affect each other's fraction unbound. For example, assume that
Drug A and Drug B are both protein-bound drugs. If Drug A is given, it will
bind to the plasma proteins in the blood. If Drug B is also given, it can
displace Drug A from the protein, thereby increasing Drug A's fraction unbound.
This may increase the effects of Drug A, since only the unbound fraction may
exhibit activity.
Q.7 Out of bound or unbound
toxicant which one is active?
Unbound
Q.8 Name the proteins to which
plasma can bind
Albumin alpha glycoproteins
Q.9 What is the problem with highly
bound toxicants?
Slowly eliminated, so linger longer
Q.10 What is the meaning of
Kernicterus?
Kernicterus is a bilirubin-induced brain
dysfunction. Bilirubin is a highly neurotoxic substance that may become
elevated in the serum, a condition known as hyperbilirubinemia.
Exercise 4
Q.1 In which main tissue/ organ
biotransformation of toxicants occurs?
Liver
Q.2 In which tissue/ organ
excretion of toxicants occurs?
a)
renal
b) intestinal (bile) -fecal
c) unabsorbed -fecal
b) intestinal (bile) -fecal
c) unabsorbed -fecal
Q.3 What is elimination t1/2?
Time it takes for plasma
concentration to drop by 50%
Q.4
What are the factors that are responsible for renal reabsorption of toxicants?
a)
lipid solubility
b) weak acids/bases
c) urine pH
b) weak acids/bases
c) urine pH
Q.5
What are the factors that are responsible for biliary excretion?
i) enterohepatic recirculation
ii) glucocorinide conjugates
ii) glucocorinide conjugates
Q.6
Name the solute carrier proteins (SLC) family.
i) oats (organic anion
transporters)
ii) octs (organic cation transporters)
iii) oatps (organic anion transporter polypeptides)
ii) octs (organic cation transporters)
iii) oatps (organic anion transporter polypeptides)
Q.
7 Name main sites for biotransformation.
i) liver
ii) lung
iii) kidney
iv) also skin, intestine, testes, placenta
iv) also skin, intestine, testes, placenta
Q.8
What is the outcome of biotransformations?
i) detoxification (inactivation)
ii) bioactivation
iii) facilitate excretion
ii) bioactivation
iii) facilitate excretion
Q.9
What are phase 1 biotransformation reactions?
i) simple degradation reactions
ii) ATP dependent add or expose a
functional group such as -hydorxyl, carboxyl and amino.
Q.10
Write phase 1 biotransformation reactions.
i) Includes oxidative
ii) reductive
iii) and hydrolytic reactions.
Exercise 5
Q.1 During phase 1 reactions: uses
what enzymes
Cytochrome P450
Q.2 During oxidation
biotransformation (phase 1) cytochrome b contains what?
Fe- containing heme proteins
Q.3 Where cytochrome P450 enzymes
are located?
ER membrane (mutiple isoforms)
(broad range of substrates)
Q.4 What happens (reactions) during
biotransformation phase II?
i) conjugation
reactions that are ATP dependent (alteration
of chemicals)
ii) renders non polar compounds to polar
iii) promote excretion (larger, charged, water soluble)
Q.
5 Name phase II conjugation reactions and their location
i) glucoronidation (ER)
ii) sulfation (cytosol)
iii) acetylation (cytosol)
iv) methylation (cytosol and ER)
v) glutathione conjugation (cytosol and ER)
ii) sulfation (cytosol)
iii) acetylation (cytosol)
iv) methylation (cytosol and ER)
v) glutathione conjugation (cytosol and ER)
Q.6 What is the influence of route of administration of
drug/toxicant on bioavailability?
It is generally in the following order:
IV > oral route
> topical route
Q.7 Define volume of distribution (Vd)
The total volume of fluid in which
a toxic substance must be dissolved to account for the measured plasma concentrations
is known as the apparent volume of distribution (Vd).
To be cont'd
FURTHER READING
Gupta P.K
(2010): Absorption, Distribution, & Excretion of Xenobiotics. In:
Gupta, PK (Ed.) Modern Toxicology: Basis of Organ and
Reproduction Toxicity, Vol. 1, (ed PK Gupta), 2nd
reprint (pp 71-92) PharmaMed Press, Hyderabad, India.
Gupta P.K. (2014)
Essential concept in toxicology. 1st Ed. BSP, Hyderabad, India
(chapter 7)
Gupta P.K. (2016)
Fundamental of Toxicology: Essential concept and applications. Elsevier/BSP San
Diego, USA (Chapter 8)
Gupta PK (2018)
Illustrative Toxicology: 1st
Edition. Elsevier, San Diego, USA.
Krishnamurti, C. R
(2010): Biotransformation of Xenobiotics. In: Gupta, PK (Ed.) Modern
Toxicology: Basis of Organ and Reproduction Toxicity, Vol. 1 (ed PK Gupta), 2nd
reprint (pp 95-129). PharmaMed Press,
Hyderabad, India.
Lehman-McKeeman, Lois D. (2015) Absorption, Distribution, and Excretion of Toxicants. In: Casarett
& Doull’s Essentials of Toxicology, Curtis D Klaassen. Watkins III John B
(ed). 3rd ed. McGraw-Hill,
USA pp, 61-78.
Parkinson A, Brian W. Ogilvie, David
B. Buckley, Faraz Kazmi, Maciej Czerwinski, Oliver Parkinson (2015). Biotranstormation of Xenobiotics. In: Casarett & Doull’s Essentials of
Toxicology. Curtis D. Klaassen Watkins III John B (ed). 3rd ed. McGraw-Hill, USA pp,
79-108.
