BIOPHARMACEUTICS AND PHARMACOKINETICS - ASSIGNMENT QUESTIONS

Introduction to Biopharmaceutics and Drug Absorption

S. No.
Short Answer Questions
 Define the following terms:

Biopharmaceutics

Drug Absorption process

Bioavailability

Pharmacokinetics

Pharmacokinetic parameters – Peak plasma concentration (Cmax)

Time of peak plasma concentration (Tmax)

Area under curve (AUC)

Pharmacodynamic

Pharmacodynamic parameters – Minimum effective concentration (MEC)

Maximum Safe Concentration (MSC)

Onset of Action

Onset of time
1
Duration of time and Intensity of action

Therapeutic Range/Therapeutic Window

Therapeutic Index

Clinical Pharmacokinetics

Pre-systemic Metabolism/First pass effect

Drug Disposition

Drug distribution

Elimination

Biotransformation

Excretion

Apparent volume of distribution

Protein binding of drugs

Xenobiotics
 Long answer Questions

Draw a neat labeled diagram of Cell membrane and emphasize a brief note on its
structure and physiology that effects drug absorption process.

Illustrate the various mechanisms involved in drug absorption process with a neat
labeled diagram.

Explain in detail about passive diffusion process, ion pair transport and pore
transport involved in drug absorption process.

Explain in detail about carrier mediated transport, facilitated diffusion, active

transport and endocytosis involved in drug absorption process with neat labeled
diagrams.

Recall various phases and routes involved in drug transfer from GI absorption
site in to systemic circulation

Classify various factors affecting drug absorption process and summarize a brief
note how physicochemical properties of drug such as polymorphism, amorphism
and pseudopolymorphism affect drug absorption process.

Summarize a brief note how physicochemical properties of drug such as Particle

size and effective surface area, Salt form of drug affect drug absorption process
with neat labeled diagram.

Recall and relate how pH partition hypothesis affects drug absorption process.
Outline the limitations of pH partition hypothesis.

Define Drug Solubility and dissolution rate. Demonstrate various dissolution

theories involved in drug absorption process.

How disintegration time , dissolution time, nature and type of dosage form
(pharmacotechnical factors) affects drug absorption process

How manufacturing variables and pharmaceutical ingredients as

pharmacotechnical factors affects drug absorption process

Outline a brief note on age, Gastric emptying time, Intestinal transit time, G.I pH
and disease state as a patient related factors affects drug absorption process

Outline a brief note on blood flow to GIT, Gastrointestinal contents and pre-
systemic metabolism as a patient related factors affects drug absorption process

2 Explain in detail about various miscellaneous factors affecting drug distribution

Enlist and explain in detail with neatly labeled diagrams of various
physiological barriers involved in distribution of drugs

Explain in detail about binding of drugs to blood components

Explain in detail about binding of drugs to Extravascular tissue components

Explain briefly about various factors affecting protein – drug binding

Outline in detail about significance of protein/tissue binding of drugs

Illustrate in detail the kinetics of protein – drug binding with help of different
plots

Enlist various pathways involved in Phase – I reactions and write in detail about
how oxidative reactions involved in biotransformation of drugs.

Enlist various pathways involved in Phase – I reactions and write in detail about
how Reductive reactions involved in biotransformation of drugs.

Enlist various pathways involved in Phase – I reactions and write in detail about
how Hydrolytic reactions involved in biotransformation of drugs.

Enlist various pathways involved in Phase – II reactions and write in detail about
how conjugation with glucuronic acid reactions involved in biotransformation of
drugs.

Enlist various pathways involved in Phase – II reactions and write in detail about
how conjugation with sulphate meioties and with alpha amino acids reactions
involved in biotransformation of drugs.

Enlist various pathways involved in Phase – II reactions and write in detail about
how conjugation with glutathione and mercapturic acids reactions involved in
biotransformation of drugs.

Enlist various pathways involved in Phase – II reactions and write in detail about
how acetylation and methylation reactions involved in biotransformation of
drugs.

Explain various biological factors affecting drug biotransformation.

Enlist various pathways involved in Phase – II reactions
Example of a Phase-II reaction
Phase-II Reaction
Once polar functional groups are placed into the molecule by the Phase-I reactions, phase-II
reaction occurs. In phase-II reactions the drugs or metabolites
COOH(from phase-I reactions) are
conjugated with suitable moiety such as glucuronic acid, sulfate, glycine, HO
etc. in presence of
O
enzyme transferase. Phase-II reactions forms highly polar, readily + excretable HOOC
and
OH
pharmacologically inert products. HO O-UDP
Phase-II reactions are as follows: Salicylic acid
OH
Uridine diphosphoglucuronic acid
Glucuronide conjugation
Ether glucuronide Glucuronidation
Ester glucuronide COOH
O
HO
OH
HO O OC

OH
Glucuronide of salicylic acid
 Amide glucuronide
Peptide conjugation
Glycine conjugation (hippurate)]
Methylation
N-methylation
O-methylation
Acetylation
Sulphate conjugation
Mercapturic acid synthesis

Explain various physicochemical properties and chemical factors affecting drug

biotransformation.

Ans: Physicochemical properties of the drug biotransformation includes:

Molecular size and shape, pKa, Acidity/basicity, lipophilicity and steric factors and
electronic characteristics of a drug influence in interaction with the active sites of enzyme and
the metabolism to which it is subjected. However such an interrelationship is not clearly
understood. Conclusion: The therapeutic efficacy, toxicity and biological half-life of a drug
greatly depend on the metabolism of the drug and a number of factors affect the metabolism of
the drug. Hence various factors affecting drug metabolism must be considered during
administration and also in proper dosing of any drug to the patients.

Explain various biological factors affecting drug biotransformation.

Biological factors

a. Age:
 The drug metabolic rate in the different age groups differs mainly due to variations in the
enzyme content, enzyme activity and haemodynamics. & Starvation results in decreased amount
of glucuronides formed than under normal conditions. Dietary deficiency of vitamins like
Vitamin A, B2, B3, C and E) and minerals such as Fe, Ca, Mg, Zn retard the metabolic activity
of enzymes.

Grapefruit inhibits metabolism of many drugs and improve their oral bioavailability. Fat
free diet depresses cytochrome P-450 levels since phospholipids, which are important
components of microsomes become deficient.

Low protein diet decreases and high protein diet increases the drug metabolizing ability
as enzyme synthesis is promoted by protein diet and also raises the level of amino acids for
conjugation with drugs.

In elderly persons, the liver size is reduced, the microsomal enzyme activity is decreased
and hepatic blood flow also declines as a result of reduced cardiac output, all of which
contributes to decreased metabolism of drugs.

For example, chlomethiazole shows a high bioavailability within the elderly, therefore
they require a lower dose.

b. Diet: The enzyme content and activity is altered by a number of dietary components.
Generally Children (between 1 year and 12 years) metabolize several drugs much more rapidly
than adults as the rate of metabolism reaches a maximum somewhere between 6 months and 12
years. As a result they require large mg/kg dose in comparison to adults.

c. Sex difference: Since variations between male and female are observed following puberty. So,
sex related differences in the rate of metabolism may be due to sex hormones. Such sex
differences are widely studied in rats where male rats have greater drug metabolizing capacity. In
humans, women metabolize benzodiazepines slowly than men. Several studies have shown that
women on contraceptive pills metabolize a number of drugs at a slow rate. [5] 5

d. Species difference: Species difference have been observed in both Phase-I and Phase-II
reactions. In Phase-I reactions, both qualitative and quantitative variations in the enzyme and
their activity have been observed. Qualitative differences among species generally result from
the presence or absence of specific enzymes in those species. Quantitative differences result from
variations in the amount and localization of enzymes, the amount of natural inhibitors, and the
competition of enzymes for specific substrates. Human liver contains less cytochrome P-450 per
gram of tissue than do the livers of other species. For example, rat liver contains approximately
30 to 50 nmol/g of Cytochrome P450, whereas human liver contains 10 to 20 nmol/g.
Furthermore, human liver is 2 percent of body weight, whereas rat liver is approximately 4
percent. Similarly,In men, amphetamine and ephedrine are predominantly metabolized by
oxidative deamination, whereas in rats aromatic oxidation is the major route in Phase-II
reactions. Similarly in pigs, the phenol is excreted mainly as glucuronide whereas its sulphate
conjugate dominates in cats.

e. Strain difference: Just as the difference in drug metabolising ability between different species
is attributed to genetics, the differences are observed between strains of same species also. It may
be studied under two headings: Pharmacogenetics: A study of inter-subject variability in drug
response is called pharmacogenetics. The inter-suject variations in metabolism may either be
monogenetically or polygenetically controlled. A polygenetic control is observed in twins. In
identical twins (monozygotic), very little or no difference in metabolism of halothane,
phenylbutazone, dicoumaral and antipyrine was detected but large variations were observed in
fraternal twins (dizygotic). Ethnic variations: Differences observed in the metabolism of drug
among different races are called ethnic variations. Such variations may be monomorphic or
polymorphic. Example: Approximately equal percent of slow and rapid acetylators are found
among whites and blacks whereas the slow acetylators dominate Japanese and Eskimo
population.

f. Altered physiological factors:

i. Pregnancy:

Pregnancy is known to affect hepatic drug metabolism. Physiological changes during

pregnancy are probably responsible for the reported alteration in drug metabolism. These
Hypoalbuminaemia (leading to lower plasma binding of drugs). For example: glycine
conjugation of salicylates, oxidation of Vitamin D and hydrolysis of procaine are impaired in
kidney diseases. iii. Hormonal imbalance higher level of one hormone may inhibit the activity of
few enzymes while inducing that of others. Adrenolectomy, thyroidectomy and alloxan-induced
diabetes in animals showed impairment in the enzyme activity with subsequent fall in the rate of
metabolism. A similar effect was also observed in the pituitary growth hormone and stress related
changes in ACTH levels. 3. Physicochemical properties of the drug Molecular size and shape,
pKa, acidity/basicity,lipophilicity and steric and electronic characteristics of a drug influence in
interaction with the active sites of enzyme and the metabolism to which it is subjected. However
such an interrelationship is not clearly understood. Conclusion Altered hepatic blood flow.

Decreased enzyme activity in liver include elevated concentrations of various hormones

such as estrogen, progesterone, placental growth hormones and prolactin. For example: in
women, the metabolism of promazine and pethidine is reduced during pregnancy. It was also
confirmed by the study in animals. In pregnant Sprague-Dawley rats, hexobarbital
biotransformation indicated unchanged or slightly elevated microsomal enzyme activity
compared to normal rats.

ii. Disease states: There are many disease states that affect the metabolism of drugs.
Some of them are cirrhosis of liver, alcoholic liver disease, cholestatic jaundice, diabetes
mellitus, acromegaly, malaria, various bacterial and viral infections, etc. It can be seen that major
effects are seen in the disease affecting liver as liver is quantitatively the important site for
metabolism. The possible cause in the effect of metabolism due to diseases may be: sion The
therapeutic efficacy, toxicity and biological half-life of a drug greatly depends on the metabolism
of the drug and a number of factors affect the metabolism of the drug. Hence various factors
affecting drug metabolism must be considered during administration and also in proper dosing of
any drug to the patients.